{"gene":"REN","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2010,"finding":"REN(KCTD11) forms an E3 ubiquitin ligase complex with Cullin3 that targets HDAC1 for degradation. Loss of HDAC1 prevents deacetylation of Gli1/Gli2, thereby suppressing Hedgehog pathway transcriptional activation. Gli1 and Gli2 were shown to be acetylated proteins whose deacetylation by HDAC1 promotes transcriptional activation; abrogation of Gli1 acetylation enhances proliferation and transformation.","method":"Co-immunoprecipitation, ubiquitin ligase assay, acetylation assays, overexpression and knockdown experiments in neural progenitor and medulloblastoma cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying the Cullin3-REN complex, functional acetylation assays on Gli proteins, loss-of-function and gain-of-function experiments with defined molecular readouts, published in high-impact peer-reviewed journal","pmids":["20081843"],"is_preprint":false},{"year":2004,"finding":"REN(KCTD11) suppresses Hedgehog signaling by antagonizing Gli-mediated transactivation of Hedgehog target genes and by affecting Gli1 nuclear transfer. REN inhibits medulloblastoma cell proliferation and colony formation in vitro and suppresses xenograft tumor growth in vivo; its growth-inhibitory activity is impaired by Gli1 inactivation (epistasis).","method":"Luciferase reporter assays for Gli-mediated transcription, nuclear fractionation to assess Gli1 localization, colony formation assays, xenograft tumor growth, genetic epistasis with Gli1 inactivation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, nuclear fractionation, in vivo xenograft, epistasis), consistent findings across assay types in a focused mechanistic study","pmids":["15249678"],"is_preprint":false},{"year":2005,"finding":"REN(KCTD11) promotes growth arrest and apoptosis in granule cell progenitors (GCPs) by antagonizing Sonic Hedgehog (Shh) signaling: REN overexpression impairs Gli2-dependent gene transcription and Shh-enhanced Gli1 mRNA expression, increases p27/Kip1-positive GCPs, and enhances caspase-3 activation. Conversely, REN knockdown impairs Hedgehog antagonism and differentiation while sustaining GCP proliferation.","method":"Overexpression and siRNA knockdown in cultured GCPs, Gli reporter assays, RT-PCR for Gli1 target gene expression, p27/Kip1 immunostaining, TUNEL and caspase-3 activation assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional loss- and gain-of-function with multiple orthogonal readouts (proliferation, differentiation markers, apoptosis, pathway reporter), consistent with PMID 15249678 and 20081843","pmids":["16148242"],"is_preprint":false},{"year":2002,"finding":"REN (KCTD11) is a developmentally regulated gene that promotes neural cell differentiation: REN overexpression induces neuronal differentiation, growth arrest, and p27Kip1 expression in CNS and PNS neural progenitor cell lines. REN inhibition impairs retinoic acid induction of neurogenin-1 and NeuroD expression. REN is upregulated by neurogenic signals (retinoic acid, EGF, NGF) in embryonal stem cells.","method":"Overexpression and antisense inhibition in neural progenitor cell lines, RT-PCR for neurogenic markers (neurogenin-1, NeuroD), p27Kip1 immunostaining, in situ hybridization in mouse embryo","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined molecular markers in neural progenitors, single laboratory study with multiple readouts","pmids":["12186855"],"is_preprint":false},{"year":1990,"finding":"Expression of the mouse Ren-2 renin gene in transgenic rats causes severe hypertension despite low levels of active plasma renin and without overexpression of active renin in the kidney, demonstrating that extrarenal Ren-2 expression is sufficient to drive hypertension through the renin-angiotensin system.","method":"Transgenic rat model (pronuclear injection of mouse Ren-2 gene), blood pressure measurement, renin activity assay in plasma and kidney","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct genetic causation established in transgenic animal model with blood pressure and renin measurements; widely replicated by multiple subsequent labs","pmids":["2181319"],"is_preprint":false},{"year":1992,"finding":"The mouse Ren-2 transgene is expressed in vascular tissue (mesenteric and aortic) of transgenic rats and is responsible for substantially increased vascular angiotensin I and II formation, as shown by ex vivo hindquarter perfusion and RNase protection/Northern blot detection of Ren-2 mRNA in vascular tissue. Bilateral nephrectomy abolished angiotensin release from control but not transgenic hindlimbs, confirming extrarenal vascular renin-2 as the source.","method":"Isolated perfused hindquarter preparation with HPLC/radioimmunoassay of angiotensin peptides, bilateral nephrectomy, RNase protection assay and Northern blot for Ren-2 mRNA in vascular tissue","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional ex vivo assay combined with molecular detection of transgene expression in vascular tissue, nephrectomy control ruling out renal origin","pmids":["1592469"],"is_preprint":false},{"year":1985,"finding":"Both Ren-1 and Ren-2 loci are expressed in the kidney of two-gene mouse strains, with Ren-1 and Ren-2 mRNAs accumulating to approximately equal levels, as determined by allele-specific primer extension assays.","method":"Reverse transcriptase-mediated primer extension with allele-specific oligonucleotide primers and dideoxynucleotide sequencing to distinguish Ren-1 and Ren-2 transcripts in kidney","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel allele-specific molecular assay applied to kidney tissue, single laboratory, findings directly validated by the assay design","pmids":["3898081"],"is_preprint":false},{"year":1987,"finding":"Ren-2 transgene expression in transgenic mice recapitulates the correct tissue-specific pattern (kidney and submaxillary gland) and hormonal regulation (androgen-stimulated expression in submaxillary gland) when flanking sequences of 2.5 kb upstream and 3 kb downstream are included, indicating that cis-acting elements within this region govern tissue-specific and androgen-regulated expression. One difference noted: basal Ren-2 expression in SMG of transgenic females was lower, suggesting additional cis-acting elements outside the injected fragment are needed for full basal expression.","method":"Pronuclear microinjection transgenic mouse lines, Northern blot analysis of tissue-specific expression, androgen treatment of female transgenic mice","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional test of promoter/enhancer region activity via transgenic complementation, multiple independent transgenic lines examined","pmids":["3297677"],"is_preprint":false},{"year":1989,"finding":"Expression of the DBA/2J Ren-2 gene in the adrenal gland X-zone is restricted by cell-type-specific regulation that requires at least one additional trans-acting locus, as demonstrated by the fact that the DBA/2-derived Ren-2 transgene in Ren-1c/Ren-1c mice is restricted to the X-zone while in native DBA/2 mice expression cycles between X-zone and zona fasciculata during oestrus.","method":"Transgenic mouse lines, tissue RNA analysis, genetic crosses to assess trans-acting regulation","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation approach demonstrating trans-regulation of tissue-specific expression, single laboratory","pmids":["2480233"],"is_preprint":false},{"year":1984,"finding":"Comparative sequence analysis of Ren-1 and Ren-2 5'-proximal flanking regions revealed strong conservation of eucaryotic transcription consensus sequences and transcription initiation sites, with significant sequence divergence ~150 bp upstream including a repetitive DNA element (IAP retroviral-like insertion) specific to Ren-2, suggesting that differential tissue-specific expression arises from sequences in this divergent region.","method":"S1 nuclease mapping of transcription start sites, nucleotide sequence analysis of 5'-flanking regions, comparative genomic analysis","journal":"Molecular and cellular biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — sequence comparison and transcription mapping only; no functional mutagenesis performed to confirm regulatory role of divergent sequences","pmids":["6392850"],"is_preprint":false},{"year":2001,"finding":"Expression from the mouse Ren-1c gene requires a proximal promoter element (PPE at ~-60) that is an Abd-B class HOX.PBX binding sequence. Abd-B HOX members (HOXD10, HOXA10, HOXA9, HOXB9, HOXC9) bind the PPE and form a ternary complex with PBX1b and PREP1. Point mutations in either the HOX or PBX half-site of the PPE abolished HOX.PBX complex formation and dramatically reduced Ren-1c transcriptional activity.","method":"Electrophoretic mobility shift assay (EMSA) for protein-DNA binding, luciferase reporter assay with PPE point mutations, chromatin immunoprecipitation (in vivo binding), recombinant protein binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of HOX.PBX.PREP1 ternary complex on PPE DNA, combined with site-directed mutagenesis and reporter assays demonstrating functional necessity, single laboratory","pmids":["11432851"],"is_preprint":false},{"year":1996,"finding":"Targeted inactivation of Ren-2 in strain 129 mice demonstrated that Ren-2-null mice are viable, healthy, and show no blood pressure alteration, establishing that Ren-1d alone can maintain normal blood pressure. Ren-2-null mice have increased active renin and decreased prorenin in plasma, showing Ren-2 contributes to prorenin production.","method":"Gene targeting (homologous recombination) to inactivate Ren-2, blood pressure measurement, plasma renin and prorenin quantification, histopathological analysis","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with direct blood pressure and biochemical phenotyping, establishes functional equivalence of Ren-1d for blood pressure regulation","pmids":["8952610"],"is_preprint":false},{"year":2000,"finding":"Mice lacking functional Ren-1d exhibit a complete absence of renal juxtaglomerular cell granulation and atypical macula densa morphology. Complementation with a 145-kb BAC clone encompassing both Ren-1d and Ren-2 fully restored normal renal structure. Overexpression of renin-2 cannot compensate for loss of renin-1d, demonstrating that primary structural differences between the two isoforms are responsible for differences in juxtaglomerular cell granulation.","method":"BAC transgenic complementation of Ren-1d-null mice, histological analysis of juxtaglomerular cells, beta-galactosidase reporter (IRES-beta-geo) insertion into Ren-1d locus by homologous recombination in E. coli","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic complementation with large BAC clone, direct histological readout, null background controls, epistasis between Ren-1d and Ren-2 isoforms explicitly tested","pmids":["10995772"],"is_preprint":false},{"year":1990,"finding":"Mouse Ren-2 prorenin was purified from transfected Chinese hamster ovary (CHO) cells. The purified prorenin has a molecular mass of 42 kDa (SDS-PAGE), isoelectric point of 6.5, and an amino terminus matching the predicted sequence from preprorenin cDNA, confirming that prorenin is the secreted precursor form of Ren-2 renin.","method":"CHO cell transfection, protein purification by DEAE, Blue-Toyopearl and isoelectric focusing chromatography, SDS-PAGE, N-terminal amino acid sequencing","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct protein purification and biochemical characterization from recombinant expression system, N-terminal sequencing confirming predicted prorenin structure; single laboratory","pmids":["2202716"],"is_preprint":false},{"year":2004,"finding":"Renin-expressing cells in the brain were localized to specific areas including cerebellum, hippocampus, dorsal motor nucleus of the vagus, inferior olivary nucleus, rostral ventrolateral medulla, central nucleus of the amygdala, and other cardiovascular control regions. Co-labeling showed these cells are predominantly neuronal (not glial), using an eGFP reporter driven by the mouse renin promoter.","method":"Transgenic REN-eGFP reporter mice, fluorescence microscopy, co-immunolabeling with neuron-specific (NeuN) and glia-specific (GFAP, MBP) antisera","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct reporter-based localization with cell-type co-labeling, validated transgenic model with appropriate physiological controls in kidney; single laboratory","pmids":["14625376"],"is_preprint":false},{"year":2020,"finding":"Clinical and molecular characterization of ADTKD-REN in 111 patients from 30 families revealed three pathophysiologically distinct subtypes based on mutation location: (1) Signal peptide mutations reduce hydrophobicity required for ER translocation, leading to aberrant cytoplasmic delivery of preprorenin; (2) Prosegment mutations cause prorenin/renin deposition in the ER-Golgi intermediate compartment and decreased prorenin secretion; (3) Mature renin mutations cause mutant prorenin deposition in the ER. Rate of progression to ESRD differs significantly among groups.","method":"Cohort clinical characterization combined with cell biology: ER translocation assays, subcellular fractionation, immunofluorescence localization of mutant prorenin/renin in patient-derived or transfected cells","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — large international cohort with functional mechanistic studies of signal peptide hydrophobicity and intracellular trafficking, multiple mutation classes with distinct cellular phenotypes validated by direct localization experiments","pmids":["32750457"],"is_preprint":false},{"year":1998,"finding":"The local adrenal renin-angiotensin system is functionally active in vivo: in TGR(mREN2)27 rats with high adrenal renin activity, adrenocortical steroid production is elevated and aldosterone regulation is impaired despite low plasma angiotensin and kidney renin, demonstrating that adrenal Ren-2 expression drives a local RAS independent of the systemic RAS.","method":"TGR(mREN2)27 transgenic rat model, measurement of adrenal renin activity, adrenocortical steroid production and aldosterone regulation","journal":"Hormone and metabolic research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — transgenic model with tissue-level functional readouts, single laboratory, no direct in vitro reconstitution of adrenal RAS","pmids":["9694562"],"is_preprint":false},{"year":2007,"finding":"ACE2 is the primary enzyme responsible for cardiac angiotensin II metabolism to angiotensin-(1-7) in the hypertrophic heart of Ren-2 hypertensive rats. ACE2 inhibition with MLN-4760 reduced ANG-(1-7) production by 83% in transgenic but had no significant effect in normotensive hearts, and ACE2 activity correlated with ACE2 protein expression (r=0.78).","method":"Langendorff isolated heart preparation with exogenous ANG II perfusion, ACE2 inhibitor MLN-4760, radioimmunoassay of ANG-(1-7) in cardiac effluent, ACE2 activity assay, Western blot for ACE2 protein","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic inhibition in isolated organ preparation with quantitative peptide measurement, correlation of activity with protein expression; single laboratory with multiple orthogonal methods","pmids":["17308000"],"is_preprint":false}],"current_model":"REN (renin / KCTD11) encodes two functionally distinct proteins from the same locus: (1) Renin, the rate-limiting aspartyl protease of the renin-angiotensin system that cleaves angiotensinogen to angiotensin I, whose tissue-specific expression in kidney juxtaglomerular cells, adrenal gland, brain neurons, and vasculature is controlled by HOX/PBX transcription factor complexes binding a proximal promoter element, and whose signal peptide and prosegment mutations cause distinct ER trafficking defects leading to autosomal dominant tubulointerstitial kidney disease; (2) REN/KCTD11, a Hedgehog pathway suppressor that assembles with Cullin3 to form an E3 ubiquitin ligase targeting HDAC1 for degradation, thereby preventing HDAC1-mediated deacetylation and transcriptional activation of Gli1/Gli2, and which additionally promotes neural progenitor differentiation and growth arrest through p27Kip1 induction—functions frequently lost in medulloblastoma through deletion at 17p13.2."},"narrative":{"mechanistic_narrative":"The REN locus gives rise to two functionally distinct proteins documented in this corpus. The classical product, renin, is a secreted aspartyl protease of the renin-angiotensin system whose tissue-restricted expression in kidney, vasculature, adrenal gland, and brain neurons drives angiotensin generation: extrarenal expression of the mouse Ren-2 gene is alone sufficient to produce severe hypertension by elevating vascular angiotensin I and II formation independently of renal renin [PMID:2181319, PMID:1592469], and a parallel local adrenal renin-angiotensin system drives adrenocortical steroid production and impairs aldosterone regulation [PMID:9694562]. Renin is synthesized as a secreted prorenin precursor [PMID:2202716], and its tissue-specific transcription is governed by a proximal promoter element that binds Abd-B class HOX proteins in a ternary complex with PBX1b and PREP1, with point mutations in either half-site abolishing complex assembly and transcriptional activity [PMID:11432851]. Genetic dissection of the duplicated mouse Ren-1/Ren-2 loci established that Ren-1d alone maintains normal blood pressure while Ren-2 contributes to prorenin production [PMID:8952610], and that structural differences between the isoforms determine juxtaglomerular cell granulation [PMID:10995772]. In humans, distinct REN mutations in the signal peptide, prosegment, and mature protein produce different ER and ER-Golgi trafficking defects that cause autosomal dominant tubulointerstitial kidney disease [PMID:32750457]. The second product, REN/KCTD11, is a Hedgehog pathway suppressor that assembles with Cullin3 into an E3 ubiquitin ligase targeting HDAC1 for degradation, thereby blocking HDAC1-mediated deacetylation and activation of Gli1/Gli2 [PMID:20081843]; through this antagonism of Gli transactivation it inhibits medulloblastoma growth [PMID:15249678], promotes growth arrest, apoptosis, and p27Kip1 induction in cerebellar granule cell progenitors [PMID:16148242], and drives neural progenitor differentiation [PMID:12186855].","teleology":[{"year":1984,"claim":"Before functional dissection, it was unclear what distinguished the duplicated Ren-1 and Ren-2 loci; comparative sequence analysis localized divergence to a region ~150 bp upstream containing a Ren-2-specific repetitive element, framing tissue-specific regulation as residing in proximal flanking sequence.","evidence":"S1 nuclease transcription start mapping and comparative sequence analysis of 5'-flanking regions","pmids":["6392850"],"confidence":"Low","gaps":["No functional mutagenesis was performed to confirm the regulatory role of the divergent sequences","Trans-acting factors binding the region not identified"]},{"year":1985,"claim":"To determine whether both duplicated loci are functionally transcribed in the relevant organ, allele-specific assays showed Ren-1 and Ren-2 mRNAs accumulate to roughly equal levels in kidney, establishing co-expression of the two genes.","evidence":"Allele-specific primer extension and dideoxy sequencing of kidney transcripts","pmids":["3898081"],"confidence":"Medium","gaps":["Did not address tissue-specific or hormonal differences between the loci","Protein-level contribution of each locus unresolved"]},{"year":1987,"claim":"It was unknown which sequences confer tissue-specific and hormonal control; transgenic complementation showed that 2.5 kb upstream and 3 kb downstream flanking sequence is sufficient to recapitulate kidney and androgen-regulated submaxillary gland expression, localizing cis-regulatory elements.","evidence":"Pronuclear microinjection transgenic mouse lines with Northern blot and androgen treatment","pmids":["3297677"],"confidence":"Medium","gaps":["Full basal expression required additional elements outside the fragment","Specific regulatory motifs not mapped"]},{"year":1989,"claim":"Adrenal X-zone expression was shown to depend on at least one additional trans-acting locus, demonstrating that cell-type-specific renin regulation is not autonomous to the cis-element-bearing transgene.","evidence":"Transgenic mouse lines with genetic crosses and tissue RNA analysis","pmids":["2480233"],"confidence":"Medium","gaps":["The trans-acting locus was not identified","Mechanism of X-zone restriction unknown"]},{"year":1990,"claim":"Whether renin expression outside the kidney could cause disease was unresolved; transgenic rats carrying mouse Ren-2 developed severe hypertension despite low active plasma renin, establishing that extrarenal Ren-2 expression is sufficient to drive hypertension through the RAS.","evidence":"Ren-2 transgenic rat model with blood pressure and plasma/kidney renin assays","pmids":["2181319"],"confidence":"High","gaps":["The extrarenal tissue source of the hypertensive signal was not localized in this study","Downstream angiotensin effectors not directly measured"]},{"year":1990,"claim":"To define the biochemical product of the gene, recombinant Ren-2 prorenin was purified and shown to be a 42 kDa secreted precursor with the N-terminus predicted from cDNA, confirming prorenin as the secreted precursor form of renin.","evidence":"CHO cell expression, chromatographic purification, SDS-PAGE and N-terminal sequencing","pmids":["2202716"],"confidence":"Medium","gaps":["Did not address activation/processing to mature renin in vivo","Single recombinant system"]},{"year":1992,"claim":"Building on the 1990 hypertension model, the vascular wall was identified as an extrarenal site of Ren-2 expression producing local angiotensin, since nephrectomy abolished angiotensin release from control but not transgenic hindlimbs.","evidence":"Isolated perfused hindquarter with HPLC/RIA of angiotensins, nephrectomy controls, RNase protection for vascular Ren-2 mRNA","pmids":["1592469"],"confidence":"High","gaps":["Cellular identity of vascular renin-expressing cells not defined","Contribution to systemic versus local blood pressure not partitioned"]},{"year":1996,"claim":"The relative necessity of the two duplicated loci for blood pressure was unknown; targeted Ren-2 inactivation showed null mice are normotensive, establishing that Ren-1d alone sustains blood pressure while Ren-2 contributes to prorenin production.","evidence":"Homologous-recombination knockout with blood pressure and plasma renin/prorenin phenotyping","pmids":["8952610"],"confidence":"High","gaps":["Did not address Ren-1d-specific functions","Mechanism of differential prorenin handling not resolved"]},{"year":2000,"claim":"The basis of renin isoform specialization was clarified: Ren-1d loss abolishes juxtaglomerular granulation, and BAC complementation but not Ren-2 overexpression rescued it, showing primary structural differences between isoforms determine granulation.","evidence":"BAC transgenic complementation of Ren-1d-null mice with histological analysis and locus reporter insertion","pmids":["10995772"],"confidence":"High","gaps":["Structural feature responsible for granulation differences not defined","Granule biogenesis mechanism unresolved"]},{"year":2001,"claim":"The transcriptional machinery controlling renin was defined: a proximal promoter element acts as an Abd-B class HOX.PBX site, and HOX members form a ternary complex with PBX1b and PREP1 whose disruption by half-site mutation abolishes transcription.","evidence":"EMSA, ChIP, recombinant binding assays and reporter assays with PPE point mutations","pmids":["11432851"],"confidence":"High","gaps":["Tissue-specific deployment of particular HOX members not resolved","Connection to upstream developmental signals unaddressed"]},{"year":2002,"claim":"A second, unrelated function of the locus emerged: REN/KCTD11 promotes neuronal differentiation and growth arrest via p27Kip1 induction in neural progenitors, and is required for retinoic-acid induction of neurogenic transcription factors.","evidence":"Overexpression/antisense in neural progenitor lines, RT-PCR for neurogenic markers, p27Kip1 staining, embryo in situ hybridization","pmids":["12186855"],"confidence":"Medium","gaps":["Molecular mechanism linking REN to p27Kip1 not defined here","Single laboratory study"]},{"year":2004,"claim":"REN/KCTD11 was placed in a defined oncogenic pathway: it suppresses Hedgehog signaling by antagonizing Gli-mediated transactivation and Gli1 nuclear transfer, inhibiting medulloblastoma growth in an epistatic manner with Gli1.","evidence":"Gli reporter assays, nuclear fractionation, colony formation, xenografts, Gli1-inactivation epistasis","pmids":["15249678"],"confidence":"High","gaps":["Biochemical mechanism of Gli antagonism not yet defined","Did not identify the molecular target of REN"]},{"year":2004,"claim":"To map the cellular sites of brain renin, an eGFP reporter localized renin-expressing cells to cardiovascular control regions and identified them as predominantly neuronal rather than glial.","evidence":"REN-eGFP transgenic mice with NeuN/GFAP/MBP co-immunolabeling","pmids":["14625376"],"confidence":"Medium","gaps":["Functional role of neuronal renin not established","Reporter expression may not fully recapitulate endogenous regulation"]},{"year":2005,"claim":"The cellular consequences of REN's Hedgehog antagonism were defined in cerebellar granule cell progenitors: REN impairs Gli2-dependent transcription and Shh-driven Gli1 expression while inducing p27Kip1 and caspase-3-dependent apoptosis.","evidence":"Bidirectional gain/loss-of-function in cultured GCPs with Gli reporters, RT-PCR, p27Kip1 staining, TUNEL and caspase-3 assays","pmids":["16148242"],"confidence":"High","gaps":["Did not identify the ubiquitin-ligase mechanism","In vivo cerebellar requirement not directly tested"]},{"year":2007,"claim":"In the Ren-2 hypertensive heart, the enzyme metabolizing angiotensin II to ANG-(1-7) was identified as ACE2, defining a downstream counter-regulatory arm operative in renin-driven hypertrophy.","evidence":"Langendorff isolated heart with ACE2 inhibitor MLN-4760, ANG-(1-7) RIA, ACE2 activity and Western blot","pmids":["17308000"],"confidence":"High","gaps":["Causal contribution of ANG-(1-7) to hypertrophy not tested","Single transgenic model"]},{"year":2010,"claim":"The biochemical basis of REN's Hedgehog suppression was resolved: REN/KCTD11 assembles with Cullin3 into an E3 ligase that degrades HDAC1, preventing HDAC1-mediated deacetylation and activation of Gli1/Gli2.","evidence":"Reciprocal Co-IP, ubiquitin ligase and acetylation assays, gain/loss-of-function in neural progenitor and medulloblastoma cells","pmids":["20081843"],"confidence":"High","gaps":["Structural details of the Cullin3-REN-HDAC1 complex not resolved","Regulation of the ligase activity unknown"]},{"year":2020,"claim":"The disease mechanism of human REN mutations was stratified: signal-peptide, prosegment, and mature-protein mutations produce distinct ER and ER-Golgi trafficking defects that cause ADTKD-REN with differing progression to ESRD.","evidence":"111-patient cohort with ER translocation assays, subcellular fractionation and immunofluorescence of mutant prorenin/renin","pmids":["32750457"],"confidence":"High","gaps":["How ER deposition triggers tubulointerstitial injury not fully defined","Therapeutic correction of trafficking not addressed"]},{"year":null,"claim":"It remains unresolved how the two distinct protein products of the REN locus are coordinately or independently regulated, and whether the renin-angiotensin and KCTD11-Hedgehog functions intersect within any shared cell type.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study in the corpus links the protease and Hedgehog-suppressor functions","Structural model of the Cullin3-REN E3 ligase absent","In vivo requirement of neuronal renin not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4,5,13,17]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[13,5]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,0,1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,2,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15]}],"complexes":["Cullin3-REN(KCTD11) E3 ubiquitin ligase","HOX.PBX1b.PREP1 ternary complex (on renin PPE)"],"partners":["CUL3","HDAC1","GLI1","GLI2","PBX1","PREP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P00797","full_name":"Renin","aliases":["Angiotensinogenase"],"length_aa":406,"mass_kda":45.1,"function":"Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney","subcellular_location":"Secreted; Membrane","url":"https://www.uniprot.org/uniprotkb/P00797/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/REN","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/REN","total_profiled":1310},"omim":[{"mim_id":"621396","title":"SPERMATOGENESIS-ASSOCIATED SERINE-RICH PROTEIN 1; SPATS1","url":"https://www.omim.org/entry/621396"},{"mim_id":"621355","title":"KRI1 HOMOLOG; KRI1","url":"https://www.omim.org/entry/621355"},{"mim_id":"621284","title":"GA-BINDING PROTEIN TRANSCRIPTION FACTOR, SUBUNIT BETA-2; GABPB2","url":"https://www.omim.org/entry/621284"},{"mim_id":"621227","title":"OLEOYL-ACP HYDROLASE; OLAH","url":"https://www.omim.org/entry/621227"},{"mim_id":"621217","title":"BEN DOMAIN-CONTAINING PROTEIN 6; BEND6","url":"https://www.omim.org/entry/621217"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"kidney","ntpm":134.7}],"url":"https://www.proteinatlas.org/search/REN"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P00797","domains":[{"cath_id":"2.40.70.10","chopping":"31-62_75-215","consensus_level":"high","plddt":88.1402,"start":31,"end":215},{"cath_id":"2.40.70.10","chopping":"249-404","consensus_level":"high","plddt":95.1308,"start":249,"end":404}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00797","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00797-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00797-F1-predicted_aligned_error_v6.png","plddt_mean":85.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=REN","jax_strain_url":"https://www.jax.org/strain/search?query=REN"},"sequence":{"accession":"P00797","fasta_url":"https://rest.uniprot.org/uniprotkb/P00797.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00797/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00797"}},"corpus_meta":[{"pmid":"2181319","id":"PMC_2181319","title":"Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene.","date":"1990","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2181319","citation_count":840,"is_preprint":false},{"pmid":"20081843","id":"PMC_20081843","title":"Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation.","date":"2010","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20081843","citation_count":288,"is_preprint":false},{"pmid":"15249678","id":"PMC_15249678","title":"REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15249678","citation_count":152,"is_preprint":false},{"pmid":"15494608","id":"PMC_15494608","title":"Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II 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Supplement","url":"https://pubmed.ncbi.nlm.nih.gov/1630068","citation_count":20,"is_preprint":false},{"pmid":"18372220","id":"PMC_18372220","title":"Late-onset endothelin receptor blockade in hypertensive heterozygous REN-2 transgenic rats.","date":"2008","source":"Vascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18372220","citation_count":19,"is_preprint":false},{"pmid":"12242043","id":"PMC_12242043","title":"Characterisation of a thymic renin-angiotensin system in the transgenic m(Ren-2)27 rat.","date":"2002","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/12242043","citation_count":19,"is_preprint":false},{"pmid":"19539780","id":"PMC_19539780","title":"Reduction of oxidative stress does not attenuate the development of angiotensin II-dependent hypertension in Ren-2 transgenic rats.","date":"2009","source":"Vascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19539780","citation_count":19,"is_preprint":false},{"pmid":"33233046","id":"PMC_33233046","title":"Combined transcriptomic and proteomic analysis of the response to bile stress in a centenarian-originated probiotic Lactobacillus salivarius Ren.","date":"2020","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/33233046","citation_count":18,"is_preprint":false},{"pmid":"30881303","id":"PMC_30881303","title":"Epoxyeicosatrienoic Acid-Based Therapy Attenuates the Progression of Postischemic Heart Failure in Normotensive Sprague-Dawley but Not in Hypertensive Ren-2 Transgenic Rats.","date":"2019","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30881303","citation_count":18,"is_preprint":false},{"pmid":"25237385","id":"PMC_25237385","title":"Amygdalin isolated from Semen Persicae (Tao Ren) extracts induces the expression of follistatin in HepG2 and C2C12 cell lines.","date":"2014","source":"Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25237385","citation_count":17,"is_preprint":false},{"pmid":"15126925","id":"PMC_15126925","title":"Plasma and kidney angiotensin II levels and renal functional responses to AT(1) receptor blockade in hypertensive Ren-2 transgenic rats.","date":"2004","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/15126925","citation_count":17,"is_preprint":false},{"pmid":"27916218","id":"PMC_27916218","title":"Fenofibrate Attenuates Malignant Hypertension by Suppression of the Renin-angiotensin System: A Study in Cyp1a1-Ren-2 Transgenic Rats.","date":"2016","source":"The American journal of the medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27916218","citation_count":17,"is_preprint":false},{"pmid":"2202716","id":"PMC_2202716","title":"Purification of mouse Ren 2 prorenin produced in Chinese hamster ovary cells.","date":"1990","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2202716","citation_count":17,"is_preprint":false},{"pmid":"30054426","id":"PMC_30054426","title":"20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/30054426","citation_count":17,"is_preprint":false},{"pmid":"1723718","id":"PMC_1723718","title":"A traditional Chinese herbal medicine, ren-shen-yang-rong-tang (Japanese name: ninjin-yoei-to) augments the production of granulocyte-macrophage colony-stimulating factor from human peripheral blood mononuclear cells in vitro.","date":"1991","source":"International journal of immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1723718","citation_count":17,"is_preprint":false},{"pmid":"8318591","id":"PMC_8318591","title":"Expression of the mouse Ren-1 gene in the coagulating gland: localization and regulation.","date":"1993","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/8318591","citation_count":16,"is_preprint":false},{"pmid":"28287881","id":"PMC_28287881","title":"Renin-angiotensin system blockade alone or combined with ETA receptor blockade: effects on the course of chronic kidney disease in 5/6 nephrectomized Ren-2 transgenic hypertensive rats.","date":"2017","source":"Clinical and experimental hypertension (New York, N.Y. : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/28287881","citation_count":16,"is_preprint":false},{"pmid":"1836442","id":"PMC_1836442","title":"Chain bias in Chi-stimulated heteroduplex patches in the lambda ren gene is determined by the orientation of lambda cos.","date":"1991","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1836442","citation_count":16,"is_preprint":false},{"pmid":"20537141","id":"PMC_20537141","title":"Maternal angiotensinogen (AGT) haplotypes, fetal renin (REN) haplotypes and risk of preeclampsia; estimation of gene-gene interaction from family-triad data.","date":"2010","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20537141","citation_count":15,"is_preprint":false},{"pmid":"20160196","id":"PMC_20160196","title":"Confirmation that the renin gene distal enhancer polymorphism REN-5312C/T is associated with increased blood pressure.","date":"2009","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20160196","citation_count":15,"is_preprint":false},{"pmid":"8454288","id":"PMC_8454288","title":"Linkage of Van der Woude syndrome (VWS) to REN and exclusion of the candidate gene TGFB2 from the disease locus in a large pedigree.","date":"1993","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8454288","citation_count":15,"is_preprint":false},{"pmid":"18955264","id":"PMC_18955264","title":"Oral Administration of Ren-Shen-Yang-Rong-Tang 'Ninjin'yoeito' Protects Against Hematotoxicity and Induces Immature Erythroid Progenitor Cells in 5-Fluorouracil-induced Anemia.","date":"2007","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/18955264","citation_count":15,"is_preprint":false},{"pmid":"32045853","id":"PMC_32045853","title":"Zao Ren An Shen for insomnia: a systematic review with meta-analysis.","date":"2020","source":"Sleep medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32045853","citation_count":14,"is_preprint":false},{"pmid":"9694562","id":"PMC_9694562","title":"Adrenal renin expression and its role in ren-2 transgenic rats TGR(mREN2)27.","date":"1998","source":"Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme","url":"https://pubmed.ncbi.nlm.nih.gov/9694562","citation_count":14,"is_preprint":false},{"pmid":"16807127","id":"PMC_16807127","title":"Early-onset endothelin receptor blockade in hypertensive heterozygous Ren-2 rats.","date":"2006","source":"Vascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16807127","citation_count":14,"is_preprint":false},{"pmid":"26713567","id":"PMC_26713567","title":"NADPH oxidase activity and reactive oxygen species production in brain and kidney of adult male hypertensive Ren-2 transgenic rats.","date":"2015","source":"Physiological research","url":"https://pubmed.ncbi.nlm.nih.gov/26713567","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54978,"output_tokens":5244,"usd":0.121797,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13659,"output_tokens":5368,"usd":0.101248,"stage2_stop_reason":"end_turn"},"total_usd":0.223045,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"REN(KCTD11) forms an E3 ubiquitin ligase complex with Cullin3 that targets HDAC1 for degradation. Loss of HDAC1 prevents deacetylation of Gli1/Gli2, thereby suppressing Hedgehog pathway transcriptional activation. Gli1 and Gli2 were shown to be acetylated proteins whose deacetylation by HDAC1 promotes transcriptional activation; abrogation of Gli1 acetylation enhances proliferation and transformation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin ligase assay, acetylation assays, overexpression and knockdown experiments in neural progenitor and medulloblastoma cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying the Cullin3-REN complex, functional acetylation assays on Gli proteins, loss-of-function and gain-of-function experiments with defined molecular readouts, published in high-impact peer-reviewed journal\",\n      \"pmids\": [\"20081843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"REN(KCTD11) suppresses Hedgehog signaling by antagonizing Gli-mediated transactivation of Hedgehog target genes and by affecting Gli1 nuclear transfer. REN inhibits medulloblastoma cell proliferation and colony formation in vitro and suppresses xenograft tumor growth in vivo; its growth-inhibitory activity is impaired by Gli1 inactivation (epistasis).\",\n      \"method\": \"Luciferase reporter assays for Gli-mediated transcription, nuclear fractionation to assess Gli1 localization, colony formation assays, xenograft tumor growth, genetic epistasis with Gli1 inactivation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, nuclear fractionation, in vivo xenograft, epistasis), consistent findings across assay types in a focused mechanistic study\",\n      \"pmids\": [\"15249678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"REN(KCTD11) promotes growth arrest and apoptosis in granule cell progenitors (GCPs) by antagonizing Sonic Hedgehog (Shh) signaling: REN overexpression impairs Gli2-dependent gene transcription and Shh-enhanced Gli1 mRNA expression, increases p27/Kip1-positive GCPs, and enhances caspase-3 activation. Conversely, REN knockdown impairs Hedgehog antagonism and differentiation while sustaining GCP proliferation.\",\n      \"method\": \"Overexpression and siRNA knockdown in cultured GCPs, Gli reporter assays, RT-PCR for Gli1 target gene expression, p27/Kip1 immunostaining, TUNEL and caspase-3 activation assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional loss- and gain-of-function with multiple orthogonal readouts (proliferation, differentiation markers, apoptosis, pathway reporter), consistent with PMID 15249678 and 20081843\",\n      \"pmids\": [\"16148242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"REN (KCTD11) is a developmentally regulated gene that promotes neural cell differentiation: REN overexpression induces neuronal differentiation, growth arrest, and p27Kip1 expression in CNS and PNS neural progenitor cell lines. REN inhibition impairs retinoic acid induction of neurogenin-1 and NeuroD expression. REN is upregulated by neurogenic signals (retinoic acid, EGF, NGF) in embryonal stem cells.\",\n      \"method\": \"Overexpression and antisense inhibition in neural progenitor cell lines, RT-PCR for neurogenic markers (neurogenin-1, NeuroD), p27Kip1 immunostaining, in situ hybridization in mouse embryo\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined molecular markers in neural progenitors, single laboratory study with multiple readouts\",\n      \"pmids\": [\"12186855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Expression of the mouse Ren-2 renin gene in transgenic rats causes severe hypertension despite low levels of active plasma renin and without overexpression of active renin in the kidney, demonstrating that extrarenal Ren-2 expression is sufficient to drive hypertension through the renin-angiotensin system.\",\n      \"method\": \"Transgenic rat model (pronuclear injection of mouse Ren-2 gene), blood pressure measurement, renin activity assay in plasma and kidney\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct genetic causation established in transgenic animal model with blood pressure and renin measurements; widely replicated by multiple subsequent labs\",\n      \"pmids\": [\"2181319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The mouse Ren-2 transgene is expressed in vascular tissue (mesenteric and aortic) of transgenic rats and is responsible for substantially increased vascular angiotensin I and II formation, as shown by ex vivo hindquarter perfusion and RNase protection/Northern blot detection of Ren-2 mRNA in vascular tissue. Bilateral nephrectomy abolished angiotensin release from control but not transgenic hindlimbs, confirming extrarenal vascular renin-2 as the source.\",\n      \"method\": \"Isolated perfused hindquarter preparation with HPLC/radioimmunoassay of angiotensin peptides, bilateral nephrectomy, RNase protection assay and Northern blot for Ren-2 mRNA in vascular tissue\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional ex vivo assay combined with molecular detection of transgene expression in vascular tissue, nephrectomy control ruling out renal origin\",\n      \"pmids\": [\"1592469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Both Ren-1 and Ren-2 loci are expressed in the kidney of two-gene mouse strains, with Ren-1 and Ren-2 mRNAs accumulating to approximately equal levels, as determined by allele-specific primer extension assays.\",\n      \"method\": \"Reverse transcriptase-mediated primer extension with allele-specific oligonucleotide primers and dideoxynucleotide sequencing to distinguish Ren-1 and Ren-2 transcripts in kidney\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel allele-specific molecular assay applied to kidney tissue, single laboratory, findings directly validated by the assay design\",\n      \"pmids\": [\"3898081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Ren-2 transgene expression in transgenic mice recapitulates the correct tissue-specific pattern (kidney and submaxillary gland) and hormonal regulation (androgen-stimulated expression in submaxillary gland) when flanking sequences of 2.5 kb upstream and 3 kb downstream are included, indicating that cis-acting elements within this region govern tissue-specific and androgen-regulated expression. One difference noted: basal Ren-2 expression in SMG of transgenic females was lower, suggesting additional cis-acting elements outside the injected fragment are needed for full basal expression.\",\n      \"method\": \"Pronuclear microinjection transgenic mouse lines, Northern blot analysis of tissue-specific expression, androgen treatment of female transgenic mice\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional test of promoter/enhancer region activity via transgenic complementation, multiple independent transgenic lines examined\",\n      \"pmids\": [\"3297677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Expression of the DBA/2J Ren-2 gene in the adrenal gland X-zone is restricted by cell-type-specific regulation that requires at least one additional trans-acting locus, as demonstrated by the fact that the DBA/2-derived Ren-2 transgene in Ren-1c/Ren-1c mice is restricted to the X-zone while in native DBA/2 mice expression cycles between X-zone and zona fasciculata during oestrus.\",\n      \"method\": \"Transgenic mouse lines, tissue RNA analysis, genetic crosses to assess trans-acting regulation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation approach demonstrating trans-regulation of tissue-specific expression, single laboratory\",\n      \"pmids\": [\"2480233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"Comparative sequence analysis of Ren-1 and Ren-2 5'-proximal flanking regions revealed strong conservation of eucaryotic transcription consensus sequences and transcription initiation sites, with significant sequence divergence ~150 bp upstream including a repetitive DNA element (IAP retroviral-like insertion) specific to Ren-2, suggesting that differential tissue-specific expression arises from sequences in this divergent region.\",\n      \"method\": \"S1 nuclease mapping of transcription start sites, nucleotide sequence analysis of 5'-flanking regions, comparative genomic analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — sequence comparison and transcription mapping only; no functional mutagenesis performed to confirm regulatory role of divergent sequences\",\n      \"pmids\": [\"6392850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Expression from the mouse Ren-1c gene requires a proximal promoter element (PPE at ~-60) that is an Abd-B class HOX.PBX binding sequence. Abd-B HOX members (HOXD10, HOXA10, HOXA9, HOXB9, HOXC9) bind the PPE and form a ternary complex with PBX1b and PREP1. Point mutations in either the HOX or PBX half-site of the PPE abolished HOX.PBX complex formation and dramatically reduced Ren-1c transcriptional activity.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA) for protein-DNA binding, luciferase reporter assay with PPE point mutations, chromatin immunoprecipitation (in vivo binding), recombinant protein binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of HOX.PBX.PREP1 ternary complex on PPE DNA, combined with site-directed mutagenesis and reporter assays demonstrating functional necessity, single laboratory\",\n      \"pmids\": [\"11432851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Targeted inactivation of Ren-2 in strain 129 mice demonstrated that Ren-2-null mice are viable, healthy, and show no blood pressure alteration, establishing that Ren-1d alone can maintain normal blood pressure. Ren-2-null mice have increased active renin and decreased prorenin in plasma, showing Ren-2 contributes to prorenin production.\",\n      \"method\": \"Gene targeting (homologous recombination) to inactivate Ren-2, blood pressure measurement, plasma renin and prorenin quantification, histopathological analysis\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with direct blood pressure and biochemical phenotyping, establishes functional equivalence of Ren-1d for blood pressure regulation\",\n      \"pmids\": [\"8952610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mice lacking functional Ren-1d exhibit a complete absence of renal juxtaglomerular cell granulation and atypical macula densa morphology. Complementation with a 145-kb BAC clone encompassing both Ren-1d and Ren-2 fully restored normal renal structure. Overexpression of renin-2 cannot compensate for loss of renin-1d, demonstrating that primary structural differences between the two isoforms are responsible for differences in juxtaglomerular cell granulation.\",\n      \"method\": \"BAC transgenic complementation of Ren-1d-null mice, histological analysis of juxtaglomerular cells, beta-galactosidase reporter (IRES-beta-geo) insertion into Ren-1d locus by homologous recombination in E. coli\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic complementation with large BAC clone, direct histological readout, null background controls, epistasis between Ren-1d and Ren-2 isoforms explicitly tested\",\n      \"pmids\": [\"10995772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Mouse Ren-2 prorenin was purified from transfected Chinese hamster ovary (CHO) cells. The purified prorenin has a molecular mass of 42 kDa (SDS-PAGE), isoelectric point of 6.5, and an amino terminus matching the predicted sequence from preprorenin cDNA, confirming that prorenin is the secreted precursor form of Ren-2 renin.\",\n      \"method\": \"CHO cell transfection, protein purification by DEAE, Blue-Toyopearl and isoelectric focusing chromatography, SDS-PAGE, N-terminal amino acid sequencing\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct protein purification and biochemical characterization from recombinant expression system, N-terminal sequencing confirming predicted prorenin structure; single laboratory\",\n      \"pmids\": [\"2202716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Renin-expressing cells in the brain were localized to specific areas including cerebellum, hippocampus, dorsal motor nucleus of the vagus, inferior olivary nucleus, rostral ventrolateral medulla, central nucleus of the amygdala, and other cardiovascular control regions. Co-labeling showed these cells are predominantly neuronal (not glial), using an eGFP reporter driven by the mouse renin promoter.\",\n      \"method\": \"Transgenic REN-eGFP reporter mice, fluorescence microscopy, co-immunolabeling with neuron-specific (NeuN) and glia-specific (GFAP, MBP) antisera\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct reporter-based localization with cell-type co-labeling, validated transgenic model with appropriate physiological controls in kidney; single laboratory\",\n      \"pmids\": [\"14625376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Clinical and molecular characterization of ADTKD-REN in 111 patients from 30 families revealed three pathophysiologically distinct subtypes based on mutation location: (1) Signal peptide mutations reduce hydrophobicity required for ER translocation, leading to aberrant cytoplasmic delivery of preprorenin; (2) Prosegment mutations cause prorenin/renin deposition in the ER-Golgi intermediate compartment and decreased prorenin secretion; (3) Mature renin mutations cause mutant prorenin deposition in the ER. Rate of progression to ESRD differs significantly among groups.\",\n      \"method\": \"Cohort clinical characterization combined with cell biology: ER translocation assays, subcellular fractionation, immunofluorescence localization of mutant prorenin/renin in patient-derived or transfected cells\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large international cohort with functional mechanistic studies of signal peptide hydrophobicity and intracellular trafficking, multiple mutation classes with distinct cellular phenotypes validated by direct localization experiments\",\n      \"pmids\": [\"32750457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The local adrenal renin-angiotensin system is functionally active in vivo: in TGR(mREN2)27 rats with high adrenal renin activity, adrenocortical steroid production is elevated and aldosterone regulation is impaired despite low plasma angiotensin and kidney renin, demonstrating that adrenal Ren-2 expression drives a local RAS independent of the systemic RAS.\",\n      \"method\": \"TGR(mREN2)27 transgenic rat model, measurement of adrenal renin activity, adrenocortical steroid production and aldosterone regulation\",\n      \"journal\": \"Hormone and metabolic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — transgenic model with tissue-level functional readouts, single laboratory, no direct in vitro reconstitution of adrenal RAS\",\n      \"pmids\": [\"9694562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ACE2 is the primary enzyme responsible for cardiac angiotensin II metabolism to angiotensin-(1-7) in the hypertrophic heart of Ren-2 hypertensive rats. ACE2 inhibition with MLN-4760 reduced ANG-(1-7) production by 83% in transgenic but had no significant effect in normotensive hearts, and ACE2 activity correlated with ACE2 protein expression (r=0.78).\",\n      \"method\": \"Langendorff isolated heart preparation with exogenous ANG II perfusion, ACE2 inhibitor MLN-4760, radioimmunoassay of ANG-(1-7) in cardiac effluent, ACE2 activity assay, Western blot for ACE2 protein\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic inhibition in isolated organ preparation with quantitative peptide measurement, correlation of activity with protein expression; single laboratory with multiple orthogonal methods\",\n      \"pmids\": [\"17308000\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"REN (renin / KCTD11) encodes two functionally distinct proteins from the same locus: (1) Renin, the rate-limiting aspartyl protease of the renin-angiotensin system that cleaves angiotensinogen to angiotensin I, whose tissue-specific expression in kidney juxtaglomerular cells, adrenal gland, brain neurons, and vasculature is controlled by HOX/PBX transcription factor complexes binding a proximal promoter element, and whose signal peptide and prosegment mutations cause distinct ER trafficking defects leading to autosomal dominant tubulointerstitial kidney disease; (2) REN/KCTD11, a Hedgehog pathway suppressor that assembles with Cullin3 to form an E3 ubiquitin ligase targeting HDAC1 for degradation, thereby preventing HDAC1-mediated deacetylation and transcriptional activation of Gli1/Gli2, and which additionally promotes neural progenitor differentiation and growth arrest through p27Kip1 induction—functions frequently lost in medulloblastoma through deletion at 17p13.2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The REN locus gives rise to two functionally distinct proteins documented in this corpus. The classical product, renin, is a secreted aspartyl protease of the renin-angiotensin system whose tissue-restricted expression in kidney, vasculature, adrenal gland, and brain neurons drives angiotensin generation: extrarenal expression of the mouse Ren-2 gene is alone sufficient to produce severe hypertension by elevating vascular angiotensin I and II formation independently of renal renin [#4, #5], and a parallel local adrenal renin-angiotensin system drives adrenocortical steroid production and impairs aldosterone regulation [#16]. Renin is synthesized as a secreted prorenin precursor [#13], and its tissue-specific transcription is governed by a proximal promoter element that binds Abd-B class HOX proteins in a ternary complex with PBX1b and PREP1, with point mutations in either half-site abolishing complex assembly and transcriptional activity [#10]. Genetic dissection of the duplicated mouse Ren-1/Ren-2 loci established that Ren-1d alone maintains normal blood pressure while Ren-2 contributes to prorenin production [#11], and that structural differences between the isoforms determine juxtaglomerular cell granulation [#12]. In humans, distinct REN mutations in the signal peptide, prosegment, and mature protein produce different ER and ER-Golgi trafficking defects that cause autosomal dominant tubulointerstitial kidney disease [#15]. The second product, REN/KCTD11, is a Hedgehog pathway suppressor that assembles with Cullin3 into an E3 ubiquitin ligase targeting HDAC1 for degradation, thereby blocking HDAC1-mediated deacetylation and activation of Gli1/Gli2 [#0]; through this antagonism of Gli transactivation it inhibits medulloblastoma growth [#1], promotes growth arrest, apoptosis, and p27Kip1 induction in cerebellar granule cell progenitors [#2], and drives neural progenitor differentiation [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Before functional dissection, it was unclear what distinguished the duplicated Ren-1 and Ren-2 loci; comparative sequence analysis localized divergence to a region ~150 bp upstream containing a Ren-2-specific repetitive element, framing tissue-specific regulation as residing in proximal flanking sequence.\",\n      \"evidence\": \"S1 nuclease transcription start mapping and comparative sequence analysis of 5'-flanking regions\",\n      \"pmids\": [\"6392850\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional mutagenesis was performed to confirm the regulatory role of the divergent sequences\", \"Trans-acting factors binding the region not identified\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"To determine whether both duplicated loci are functionally transcribed in the relevant organ, allele-specific assays showed Ren-1 and Ren-2 mRNAs accumulate to roughly equal levels in kidney, establishing co-expression of the two genes.\",\n      \"evidence\": \"Allele-specific primer extension and dideoxy sequencing of kidney transcripts\",\n      \"pmids\": [\"3898081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not address tissue-specific or hormonal differences between the loci\", \"Protein-level contribution of each locus unresolved\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"It was unknown which sequences confer tissue-specific and hormonal control; transgenic complementation showed that 2.5 kb upstream and 3 kb downstream flanking sequence is sufficient to recapitulate kidney and androgen-regulated submaxillary gland expression, localizing cis-regulatory elements.\",\n      \"evidence\": \"Pronuclear microinjection transgenic mouse lines with Northern blot and androgen treatment\",\n      \"pmids\": [\"3297677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full basal expression required additional elements outside the fragment\", \"Specific regulatory motifs not mapped\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Adrenal X-zone expression was shown to depend on at least one additional trans-acting locus, demonstrating that cell-type-specific renin regulation is not autonomous to the cis-element-bearing transgene.\",\n      \"evidence\": \"Transgenic mouse lines with genetic crosses and tissue RNA analysis\",\n      \"pmids\": [\"2480233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The trans-acting locus was not identified\", \"Mechanism of X-zone restriction unknown\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Whether renin expression outside the kidney could cause disease was unresolved; transgenic rats carrying mouse Ren-2 developed severe hypertension despite low active plasma renin, establishing that extrarenal Ren-2 expression is sufficient to drive hypertension through the RAS.\",\n      \"evidence\": \"Ren-2 transgenic rat model with blood pressure and plasma/kidney renin assays\",\n      \"pmids\": [\"2181319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The extrarenal tissue source of the hypertensive signal was not localized in this study\", \"Downstream angiotensin effectors not directly measured\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"To define the biochemical product of the gene, recombinant Ren-2 prorenin was purified and shown to be a 42 kDa secreted precursor with the N-terminus predicted from cDNA, confirming prorenin as the secreted precursor form of renin.\",\n      \"evidence\": \"CHO cell expression, chromatographic purification, SDS-PAGE and N-terminal sequencing\",\n      \"pmids\": [\"2202716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not address activation/processing to mature renin in vivo\", \"Single recombinant system\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Building on the 1990 hypertension model, the vascular wall was identified as an extrarenal site of Ren-2 expression producing local angiotensin, since nephrectomy abolished angiotensin release from control but not transgenic hindlimbs.\",\n      \"evidence\": \"Isolated perfused hindquarter with HPLC/RIA of angiotensins, nephrectomy controls, RNase protection for vascular Ren-2 mRNA\",\n      \"pmids\": [\"1592469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular identity of vascular renin-expressing cells not defined\", \"Contribution to systemic versus local blood pressure not partitioned\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The relative necessity of the two duplicated loci for blood pressure was unknown; targeted Ren-2 inactivation showed null mice are normotensive, establishing that Ren-1d alone sustains blood pressure while Ren-2 contributes to prorenin production.\",\n      \"evidence\": \"Homologous-recombination knockout with blood pressure and plasma renin/prorenin phenotyping\",\n      \"pmids\": [\"8952610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address Ren-1d-specific functions\", \"Mechanism of differential prorenin handling not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The basis of renin isoform specialization was clarified: Ren-1d loss abolishes juxtaglomerular granulation, and BAC complementation but not Ren-2 overexpression rescued it, showing primary structural differences between isoforms determine granulation.\",\n      \"evidence\": \"BAC transgenic complementation of Ren-1d-null mice with histological analysis and locus reporter insertion\",\n      \"pmids\": [\"10995772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural feature responsible for granulation differences not defined\", \"Granule biogenesis mechanism unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The transcriptional machinery controlling renin was defined: a proximal promoter element acts as an Abd-B class HOX.PBX site, and HOX members form a ternary complex with PBX1b and PREP1 whose disruption by half-site mutation abolishes transcription.\",\n      \"evidence\": \"EMSA, ChIP, recombinant binding assays and reporter assays with PPE point mutations\",\n      \"pmids\": [\"11432851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific deployment of particular HOX members not resolved\", \"Connection to upstream developmental signals unaddressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"A second, unrelated function of the locus emerged: REN/KCTD11 promotes neuronal differentiation and growth arrest via p27Kip1 induction in neural progenitors, and is required for retinoic-acid induction of neurogenic transcription factors.\",\n      \"evidence\": \"Overexpression/antisense in neural progenitor lines, RT-PCR for neurogenic markers, p27Kip1 staining, embryo in situ hybridization\",\n      \"pmids\": [\"12186855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking REN to p27Kip1 not defined here\", \"Single laboratory study\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"REN/KCTD11 was placed in a defined oncogenic pathway: it suppresses Hedgehog signaling by antagonizing Gli-mediated transactivation and Gli1 nuclear transfer, inhibiting medulloblastoma growth in an epistatic manner with Gli1.\",\n      \"evidence\": \"Gli reporter assays, nuclear fractionation, colony formation, xenografts, Gli1-inactivation epistasis\",\n      \"pmids\": [\"15249678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of Gli antagonism not yet defined\", \"Did not identify the molecular target of REN\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"To map the cellular sites of brain renin, an eGFP reporter localized renin-expressing cells to cardiovascular control regions and identified them as predominantly neuronal rather than glial.\",\n      \"evidence\": \"REN-eGFP transgenic mice with NeuN/GFAP/MBP co-immunolabeling\",\n      \"pmids\": [\"14625376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of neuronal renin not established\", \"Reporter expression may not fully recapitulate endogenous regulation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The cellular consequences of REN's Hedgehog antagonism were defined in cerebellar granule cell progenitors: REN impairs Gli2-dependent transcription and Shh-driven Gli1 expression while inducing p27Kip1 and caspase-3-dependent apoptosis.\",\n      \"evidence\": \"Bidirectional gain/loss-of-function in cultured GCPs with Gli reporters, RT-PCR, p27Kip1 staining, TUNEL and caspase-3 assays\",\n      \"pmids\": [\"16148242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the ubiquitin-ligase mechanism\", \"In vivo cerebellar requirement not directly tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In the Ren-2 hypertensive heart, the enzyme metabolizing angiotensin II to ANG-(1-7) was identified as ACE2, defining a downstream counter-regulatory arm operative in renin-driven hypertrophy.\",\n      \"evidence\": \"Langendorff isolated heart with ACE2 inhibitor MLN-4760, ANG-(1-7) RIA, ACE2 activity and Western blot\",\n      \"pmids\": [\"17308000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal contribution of ANG-(1-7) to hypertrophy not tested\", \"Single transgenic model\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The biochemical basis of REN's Hedgehog suppression was resolved: REN/KCTD11 assembles with Cullin3 into an E3 ligase that degrades HDAC1, preventing HDAC1-mediated deacetylation and activation of Gli1/Gli2.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitin ligase and acetylation assays, gain/loss-of-function in neural progenitor and medulloblastoma cells\",\n      \"pmids\": [\"20081843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the Cullin3-REN-HDAC1 complex not resolved\", \"Regulation of the ligase activity unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The disease mechanism of human REN mutations was stratified: signal-peptide, prosegment, and mature-protein mutations produce distinct ER and ER-Golgi trafficking defects that cause ADTKD-REN with differing progression to ESRD.\",\n      \"evidence\": \"111-patient cohort with ER translocation assays, subcellular fractionation and immunofluorescence of mutant prorenin/renin\",\n      \"pmids\": [\"32750457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ER deposition triggers tubulointerstitial injury not fully defined\", \"Therapeutic correction of trafficking not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the two distinct protein products of the REN locus are coordinately or independently regulated, and whether the renin-angiotensin and KCTD11-Hedgehog functions intersect within any shared cell type.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No study in the corpus links the protease and Hedgehog-suppressor functions\", \"Structural model of the Cullin3-REN E3 ligase absent\", \"In vivo requirement of neuronal renin not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4, 5, 13, 17]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [13, 5]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 0, 1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 2, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\"Cullin3-REN(KCTD11) E3 ubiquitin ligase\", \"HOX.PBX1b.PREP1 ternary complex (on renin PPE)\"],\n    \"partners\": [\"CUL3\", \"HDAC1\", \"GLI1\", \"GLI2\", \"PBX1\", \"PREP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}