Affinage

REN

Renin · UniProt P00797

Length
406 aa
Mass
45.1 kDa
Annotated
2026-06-10
100 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1984 Low

    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

    PMID:6392850

    Open questions at the time
    • No functional mutagenesis was performed to confirm the regulatory role of the divergent sequences
    • Trans-acting factors binding the region not identified
  2. 1985 Medium

    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

    PMID:3898081

    Open questions at the time
    • Did not address tissue-specific or hormonal differences between the loci
    • Protein-level contribution of each locus unresolved
  3. 1987 Medium

    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

    PMID:3297677

    Open questions at the time
    • Full basal expression required additional elements outside the fragment
    • Specific regulatory motifs not mapped
  4. 1989 Medium

    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

    PMID:2480233

    Open questions at the time
    • The trans-acting locus was not identified
    • Mechanism of X-zone restriction unknown
  5. 1990 High

    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

    PMID:2181319

    Open questions at the time
    • The extrarenal tissue source of the hypertensive signal was not localized in this study
    • Downstream angiotensin effectors not directly measured
  6. 1990 Medium

    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

    PMID:2202716

    Open questions at the time
    • Did not address activation/processing to mature renin in vivo
    • Single recombinant system
  7. 1992 High

    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

    PMID:1592469

    Open questions at the time
    • Cellular identity of vascular renin-expressing cells not defined
    • Contribution to systemic versus local blood pressure not partitioned
  8. 1996 High

    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

    PMID:8952610

    Open questions at the time
    • Did not address Ren-1d-specific functions
    • Mechanism of differential prorenin handling not resolved
  9. 2000 High

    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

    PMID:10995772

    Open questions at the time
    • Structural feature responsible for granulation differences not defined
    • Granule biogenesis mechanism unresolved
  10. 2001 High

    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

    PMID:11432851

    Open questions at the time
    • Tissue-specific deployment of particular HOX members not resolved
    • Connection to upstream developmental signals unaddressed
  11. 2002 Medium

    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

    PMID:12186855

    Open questions at the time
    • Molecular mechanism linking REN to p27Kip1 not defined here
    • Single laboratory study
  12. 2004 High

    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

    PMID:15249678

    Open questions at the time
    • Biochemical mechanism of Gli antagonism not yet defined
    • Did not identify the molecular target of REN
  13. 2004 Medium

    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

    PMID:14625376

    Open questions at the time
    • Functional role of neuronal renin not established
    • Reporter expression may not fully recapitulate endogenous regulation
  14. 2005 High

    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

    PMID:16148242

    Open questions at the time
    • Did not identify the ubiquitin-ligase mechanism
    • In vivo cerebellar requirement not directly tested
  15. 2007 High

    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

    PMID:17308000

    Open questions at the time
    • Causal contribution of ANG-(1-7) to hypertrophy not tested
    • Single transgenic model
  16. 2010 High

    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

    PMID:20081843

    Open questions at the time
    • Structural details of the Cullin3-REN-HDAC1 complex not resolved
    • Regulation of the ligase activity unknown
  17. 2020 High

    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

    PMID:32750457

    Open questions at the time
    • How ER deposition triggers tubulointerstitial injury not fully defined
    • Therapeutic correction of trafficking not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0016874 ligase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 1
Partners
CUL3GLI1GLI2HDAC1PBX1PREP1
Complex memberships
Cullin3-REN(KCTD11) E3 ubiquitin ligaseHOX.PBX1b.PREP1 ternary complex (on renin PPE)

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Co-immunoprecipitation, ubiquitin ligase assay, acetylation assays, overexpression and knockdown experiments in neural progenitor and medulloblastoma cells Nature cell biology High 20081843
2004 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). Luciferase reporter assays for Gli-mediated transcription, nuclear fractionation to assess Gli1 localization, colony formation assays, xenograft tumor growth, genetic epistasis with Gli1 inactivation Proceedings of the National Academy of Sciences of the United States of America High 15249678
2005 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. 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 The Journal of neuroscience High 16148242
2002 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. 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 The Journal of cell biology Medium 12186855
1990 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. Transgenic rat model (pronuclear injection of mouse Ren-2 gene), blood pressure measurement, renin activity assay in plasma and kidney Nature High 2181319
1992 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. 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 Hypertension High 1592469
1985 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. Reverse transcriptase-mediated primer extension with allele-specific oligonucleotide primers and dideoxynucleotide sequencing to distinguish Ren-1 and Ren-2 transcripts in kidney Proceedings of the National Academy of Sciences of the United States of America Medium 3898081
1987 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. Pronuclear microinjection transgenic mouse lines, Northern blot analysis of tissue-specific expression, androgen treatment of female transgenic mice The EMBO journal Medium 3297677
1989 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. Transgenic mouse lines, tissue RNA analysis, genetic crosses to assess trans-acting regulation The EMBO journal Medium 2480233
1984 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. S1 nuclease mapping of transcription start sites, nucleotide sequence analysis of 5'-flanking regions, comparative genomic analysis Molecular and cellular biology Low 6392850
2001 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. 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 The Journal of biological chemistry High 11432851
1996 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. Gene targeting (homologous recombination) to inactivate Ren-2, blood pressure measurement, plasma renin and prorenin quantification, histopathological analysis Hypertension High 8952610
2000 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. 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 The Journal of biological chemistry High 10995772
1990 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. CHO cell transfection, protein purification by DEAE, Blue-Toyopearl and isoelectric focusing chromatography, SDS-PAGE, N-terminal amino acid sequencing Journal of biochemistry Medium 2202716
2004 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. Transgenic REN-eGFP reporter mice, fluorescence microscopy, co-immunolabeling with neuron-specific (NeuN) and glia-specific (GFAP, MBP) antisera Physiological genomics Medium 14625376
2020 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. Cohort clinical characterization combined with cell biology: ER translocation assays, subcellular fractionation, immunofluorescence localization of mutant prorenin/renin in patient-derived or transfected cells Kidney international High 32750457
1998 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. TGR(mREN2)27 transgenic rat model, measurement of adrenal renin activity, adrenocortical steroid production and aldosterone regulation Hormone and metabolic research Medium 9694562
2007 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). 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 American journal of physiology. Heart and circulatory physiology High 17308000

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 840 2181319
2010 Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nature cell biology 288 20081843
2004 REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. Proceedings of the National Academy of Sciences of the United States of America 152 15249678
2004 Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression. American journal of physiology. Endocrinology and metabolism 139 15494608
1998 Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). European journal of human genetics : EJHG 103 9887369
2006 Effect of angiotensin II blockade on a new congenic model of hypertension derived from transgenic Ren-2 rats. American journal of physiology. Heart and circulatory physiology 100 16766648
1985 Ren-1 and Ren-2 loci are expressed in mouse kidney. Proceedings of the National Academy of Sciences of the United States of America 93 3898081
2003 Dual interaction of plant PCNA with geminivirus replication accessory protein (Ren) and viral replication protein (Rep). Virology 92 12919743
1992 Increased vascular angiotensin formation in female rats harboring the mouse Ren-2 gene. Hypertension (Dallas, Tex. : 1979) 88 1592469
2003 A thermostable laccase from Streptomyces lavendulae REN-7: purification, characterization, nucleotide sequence, and expression. Bioscience, biotechnology, and biochemistry 87 14586105
2002 Attenuation of tubular apoptosis by blockade of the renin-angiotensin system in diabetic Ren-2 rats. Kidney international 79 11786082
1994 Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene. The American journal of physiology 78 8184972
1989 Expression of the DBA/2J Ren-2 gene in the adrenal gland of transgenic mice. The EMBO journal 78 2480233
1987 Regulated expression of the Ren-2 gene in transgenic mice derived from parental strains carrying only the Ren-1 gene. The EMBO journal 78 3297677
1996 The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects. American journal of hypertension 69 8735183
1996 Targeted inactivation of the Ren-2 gene in mice. Hypertension (Dallas, Tex. : 1979) 68 8952610
2013 Lactobacillus salivarius REN inhibits rat oral cancer induced by 4-nitroquioline 1-oxide. Cancer prevention research (Philadelphia, Pa.) 67 23658366
1984 Expression of tissue-specific Ren-1 and Ren-2 genes of mice: comparative analysis of 5'-proximal flanking regions. Molecular and cellular biology 67 6392850
2004 Localization of renin expressing cells in the brain, by use of a REN-eGFP transgenic model. Physiological genomics 66 14625376
2005 Hedgehog antagonist REN(KCTD11) regulates proliferation and apoptosis of developing granule cell progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 16148242
1999 Roles of AT1 and AT2 receptors in the hypertensive Ren-2 gene transgenic rat kidney. Hypertension (Dallas, Tex. : 1979) 58 9931128
1993 Ontogenetic regulation of mouse Ren-2d renin gene in transgenic hypertensive rats, TGR(mREN2)27. The American journal of physiology 57 8238495
1994 Differential regulation of central vasopressin in transgenic rats harboring the mouse Ren-2 gene. The American journal of physiology 54 8092324
2010 Inhibition of angiotensin-converting enzyme 2 exacerbates cardiac hypertrophy and fibrosis in Ren-2 hypertensive rats. American journal of hypertension 53 20300067
2014 Intrapulmonary activation of the angiotensin-converting enzyme type 2/angiotensin 1-7/G-protein-coupled Mas receptor axis attenuates pulmonary hypertension in Ren-2 transgenic rats exposed to chronic hypoxia. Physiological research 51 25194138
2002 Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene. Journal of the American Society of Nephrology : JASN 50 12397037
1984 A retroviral provirus closely associated with the Ren-2 gene of DBA/2 mice. Nucleic acids research 50 6095203
2002 REN: a novel, developmentally regulated gene that promotes neural cell differentiation. The Journal of cell biology 49 12186855
2001 An Abd-B class HOX.PBX recognition sequence is required for expression from the mouse Ren-1c gene. The Journal of biological chemistry 49 11432851
2007 Retinal dysfunction in diabetic ren-2 rats is ameliorated by treatment with valsartan but not atenolol. Investigative ophthalmology & visual science 48 17251496
2007 Primary role of angiotensin-converting enzyme-2 in cardiac production of angiotensin-(1-7) in transgenic Ren-2 hypertensive rats. American journal of physiology. Heart and circulatory physiology 47 17308000
2007 Valsartan but not atenolol improves vascular pathology in diabetic Ren-2 rat retina. American journal of hypertension 47 17386351
2006 Late-onset endothelin-A receptor blockade reduces podocyte injury in homozygous Ren-2 rats despite severe hypertension. Hypertension (Dallas, Tex. : 1979) 46 17015777
1997 Cardiovascular end-organ damage in Ren-2 transgenic rats compared to spontaneously hypertensive rats. Journal of molecular medicine (Berlin, Germany) 46 9181479
2021 Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice. Chinese medicine 44 33478552
1989 Allele-specific expression of the murine Ren-1 genes. The Journal of biological chemistry 44 2677011
2006 AT1 receptor blockade is superior to conventional triple therapy in protecting against end-organ damage in Cyp1a1-Ren-2 transgenic rats with inducible hypertension. Journal of hypertension 42 17082731
2015 Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Clinical and experimental pharmacology & physiology 41 25969338
1995 ANG II dependence of tubuloglomerular feedback responsiveness in hypertensive ren-2 transgenic rats. The American journal of physiology 40 7771510
2007 Effects of chronic cytochrome P-450 inhibition on the course of hypertension and end-organ damage in Ren-2 transgenic rats. Vascular pharmacology 38 17604232
1988 Close physical linkage of the murine Ren-1 and Ren-2 loci. Nucleic acids research 38 2833727
2006 Effects of changes in sodium balance on plasma and kidney angiotensin II levels in anesthetized and conscious Ren-2 transgenic rats. Journal of hypertension 37 16467655
2001 Effects of angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor antagonist in deoxycorticosterone acetate-salt hypertensive mice lacking Ren-2 gene. Hypertension (Dallas, Tex. : 1979) 36 11244026
2011 Inhibition of soluble epoxide hydrolase improves the impaired pressure-natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats. Journal of hypertension 34 21720266
2006 Spectroscopic characterization of the tumor antigen NY-REN-21 and identification of heterodimer formation with SCAND1. Biochemical and biophysical research communications 33 16540086
2005 The role of intrarenal angiotensin II in the development of hypertension in Ren-2 transgenic rats. Journal of hypertension 33 16003180
1989 The nucleotide sequence of a mouse renin-encoding gene, Ren-1d, and its upstream region. Gene 33 2691339
2020 An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes. Kidney international 32 32750457
2010 Similar renoprotection after renin-angiotensin-dependent and -independent antihypertensive therapy in 5/6-nephrectomized Ren-2 transgenic rats: are there blood pressure-independent effects? Clinical and experimental pharmacology & physiology 32 20880190
2005 Early endothelin-A receptor blockade decreases blood pressure and ameliorates end-organ damage in homozygous Ren-2 rats. Hypertension (Dallas, Tex. : 1979) 32 16157796
2017 The Adhesion of Lactobacillus salivarius REN to a Human Intestinal Epithelial Cell Line Requires S-layer Proteins. Scientific reports 31 28281568
2016 Intrarenal alterations of the angiotensin-converting enzyme type 2/angiotensin 1-7 complex of the renin-angiotensin system do not alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats. Clinical and experimental pharmacology & physiology 31 26833491
2011 Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension. The Journal of physiology 31 21078594
1991 Phenotypic inhibition of the renin-angiotensin system, emergence of the Ren-2 gene, and adaptive radiation of mice. General and comparative endocrinology 31 1916217
1987 Chromosome localization of the human renin gene (REN) by in situ hybridization. Cytogenetics and cell genetics 31 3297510
1994 Alterations in coronary artery vascular reactivity of hypertensive Ren-2 transgenic rats. Circulation 30 8205692
2012 Effects of combined endothelin A receptor and renin-angiotensin system blockade on the course of end-organ damage in 5/6 nephrectomized Ren-2 hypertensive rats. Kidney & blood pressure research 29 22487948
1998 Adrenal, kidney, and heart angiotensins in female murine Ren-2 transfected hypertensive rats. Peptides 28 9880073
2010 Inappropriately high circulating and intrarenal angiotensin II levels during dietary salt loading exacerbate hypertension in Cyp1a1-Ren-2 transgenic rats. Journal of hypertension 27 19927008
1997 Endothelial vasoconstrictor prostanoids modulate contractions to acetylcholine and ANG II in Ren-2 rats. The American journal of physiology 26 9038972
2010 Persistent antihypertensive effect of aliskiren is accompanied by reduced proteinuria and normalization of glomerular area in Ren-2 transgenic rats. American journal of physiology. Renal physiology 25 20668096
2006 Angiotensin II formation in the kidney and nephrosclerosis in Ren-2 hypertensive rats. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 25 16522658
2004 Blockade of endothelin receptors attenuates end-organ damage in homozygous hypertensive ren-2 transgenic rats. Kidney & blood pressure research 25 15286437
2000 Granulation rescue and developmental marking of juxtaglomerular cells using "piggy-BAC" recombination of the mouse ren locus. The Journal of biological chemistry 25 10995772
1999 Enhanced renal vascular responsiveness to angiotensin II in hypertensive ren-2 transgenic rats. The American journal of physiology 25 9950963
2018 Effect of angiotensin-converting enzyme blockade, alone or combined with blockade of soluble epoxide hydrolase, on the course of congestive heart failure and occurrence of renal dysfunction in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Physiological research 24 29527914
2015 Functional role of oppA encoding an oligopeptide-binding protein from Lactobacillus salivarius Ren in bile tolerance. Journal of industrial microbiology & biotechnology 24 25998246
2013 Addition of ET(A) receptor blockade increases renoprotection provided by renin-angiotensin system blockade in 5/6 nephrectomized Ren-2 transgenic rats. Life sciences 24 24373834
2009 Impairment of the autoregulation of renal hemodynamics and of the pressure-natriuresis relationship precedes the development of hypertension in Cyp1a1-Ren-2 transgenic rats. Journal of hypertension 24 19330918
2009 Identification and genomic location of a reniform nematode (Rotylenchulus reniformis) resistance locus (Ren ari) introgressed from Gossypium aridum into upland cotton (G. hirsutum). TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 24 19830404
2002 ReN 1869, a novel tricyclic antihistamine, is active against neurogenic pain and inflammation. European journal of pharmacology 24 11790377
1989 Effect of a traditional Chinese herbal medicine ren-shen-yang-rong-tang (Japanese name: ninjin-youei-to) on hematopoietic stem cells in mice. International journal of immunopharmacology 24 2599715
2020 Probiotic Lactobacillus salivarius Ren prevent dimethylhydrazine-induced colorectal cancer through protein kinase B inhibition. Applied microbiology and biotechnology 22 32666185
2016 Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: a study in Cyp1a1-Ren-2 transgenic rats. Journal of hypertension 21 27428043
2011 Sensitivity of global translation to mTOR inhibition in REN cells depends on the equilibrium between eIF4E and 4E-BP1. PloS one 21 22216185
2017 Oxidative stress promotes myocardial fibrosis by upregulating KCa3.1 channel expression in AGT-REN double transgenic hypertensive mice. Pflugers Archiv : European journal of physiology 20 28455747
2015 Bai-Hu-Jia-Ren-Shen-Tang Decoction Reduces Fatty Liver by Activating AMP-Activated Protein Kinase In Vitro and In Vivo. Evidence-based complementary and alternative medicine : eCAM 20 26508982
1992 Studies on blood pressure regulation in hypertensive ren-2 transgenic rats. Kidney international. Supplement 20 1630068
2009 Reduction of oxidative stress does not attenuate the development of angiotensin II-dependent hypertension in Ren-2 transgenic rats. Vascular pharmacology 19 19539780
2008 Late-onset endothelin receptor blockade in hypertensive heterozygous REN-2 transgenic rats. Vascular pharmacology 19 18372220
2002 Characterisation of a thymic renin-angiotensin system in the transgenic m(Ren-2)27 rat. Molecular and cellular endocrinology 19 12242043
2020 Combined transcriptomic and proteomic analysis of the response to bile stress in a centenarian-originated probiotic Lactobacillus salivarius Ren. Food research international (Ottawa, Ont.) 18 33233046
2019 Epoxyeicosatrienoic Acid-Based Therapy Attenuates the Progression of Postischemic Heart Failure in Normotensive Sprague-Dawley but Not in Hypertensive Ren-2 Transgenic Rats. Frontiers in pharmacology 18 30881303
2018 20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats. Bioscience reports 17 30054426
2016 Fenofibrate Attenuates Malignant Hypertension by Suppression of the Renin-angiotensin System: A Study in Cyp1a1-Ren-2 Transgenic Rats. The American journal of the medical sciences 17 27916218
2014 Amygdalin isolated from Semen Persicae (Tao Ren) extracts induces the expression of follistatin in HepG2 and C2C12 cell lines. Chinese medicine 17 25237385
2004 Plasma and kidney angiotensin II levels and renal functional responses to AT(1) receptor blockade in hypertensive Ren-2 transgenic rats. Journal of hypertension 17 15126925
1991 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. International journal of immunopharmacology 17 1723718
1990 Purification of mouse Ren 2 prorenin produced in Chinese hamster ovary cells. Journal of biochemistry 17 2202716
2017 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. Clinical and experimental hypertension (New York, N.Y. : 1993) 16 28287881
1993 Expression of the mouse Ren-1 gene in the coagulating gland: localization and regulation. Biology of reproduction 16 8318591
1991 Chain bias in Chi-stimulated heteroduplex patches in the lambda ren gene is determined by the orientation of lambda cos. Genetics 16 1836442
2010 Maternal angiotensinogen (AGT) haplotypes, fetal renin (REN) haplotypes and risk of preeclampsia; estimation of gene-gene interaction from family-triad data. BMC medical genetics 15 20537141
2009 Confirmation that the renin gene distal enhancer polymorphism REN-5312C/T is associated with increased blood pressure. Circulation. Cardiovascular genetics 15 20160196
2007 Oral Administration of Ren-Shen-Yang-Rong-Tang 'Ninjin'yoeito' Protects Against Hematotoxicity and Induces Immature Erythroid Progenitor Cells in 5-Fluorouracil-induced Anemia. Evidence-based complementary and alternative medicine : eCAM 15 18955264
1993 Linkage of Van der Woude syndrome (VWS) to REN and exclusion of the candidate gene TGFB2 from the disease locus in a large pedigree. Human genetics 15 8454288
2020 Zao Ren An Shen for insomnia: a systematic review with meta-analysis. Sleep medicine 14 32045853
2015 NADPH oxidase activity and reactive oxygen species production in brain and kidney of adult male hypertensive Ren-2 transgenic rats. Physiological research 14 26713567
2006 Early-onset endothelin receptor blockade in hypertensive heterozygous Ren-2 rats. Vascular pharmacology 14 16807127
1998 Adrenal renin expression and its role in ren-2 transgenic rats TGR(mREN2)27. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 14 9694562

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