Affinage

REN

Renin · UniProt P00797

Round 2 corrected
Length
406 aa
Mass
45.1 kDa
Annotated
2026-04-28
130 papers in source corpus 41 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Renin (REN) is an aspartyl protease that catalyzes the rate-limiting cleavage of angiotensinogen to angiotensin I, initiating the renin-angiotensin cascade that controls blood pressure, renal hemodynamics, and aldosterone secretion (PMID:2493678, PMID:2181319). Synthesized as preprorenin with a 20-residue signal peptide and 46-residue prosegment, renin undergoes signal-peptide-directed ER translocation and is converted to active renin by the convertase PC1 in a secretory-granule-dependent manner; the prosegment contains 'gate' and 'handle' regions whose displacement permits reversible non-proteolytic activation (PMID:1597471, PMID:12684512). Renin and prorenin bind the (pro)renin receptor, which increases catalytic efficiency fourfold and triggers angiotensin II–independent ERK1/2 and p38 MAPK/HSP27 signaling cascades that remodel the actin cytoskeleton (PMID:12045255, PMID:16940215). Dominant mutations in the signal peptide, prosegment, or mature renin domain cause autosomal dominant tubulointerstitial kidney disease (ADTKD-REN) through distinct ER-stress and trafficking defects, while biallelic loss-of-function mutations cause autosomal recessive renal tubular dysgenesis (PMID:19664745, PMID:32750457, PMID:16116425).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1983 High

    Determination of the full preprorenin primary structure from cDNA established that renin is synthesized as a 406-amino-acid precursor with a signal peptide and prosegment homologous to aspartyl proteinases, resolving the biosynthetic origin of circulating renin.

    Evidence cDNA library screening and nucleotide sequencing of human kidney renin mRNA

    PMID:6324167

    Open questions at the time
    • No three-dimensional structural information yet available
    • Processing mechanism of the prosegment unknown
    • Tissue-specific transcriptional regulation not addressed
  2. 1984 High

    Elucidation of the human REN gene structure (9 exons, single copy, ~12 kb) and comparative analysis of mouse Ren-1/Ren-2 loci revealed conserved organization with divergent 5′-flanking regions, providing the framework for understanding tissue-specific and allele-specific transcriptional regulation.

    Evidence Genomic DNA cloning, restriction mapping, and complete sequencing of human and mouse renin loci; S1 nuclease mapping of transcription start sites

    PMID:6089171 PMID:6391881 PMID:6392850

    Open questions at the time
    • Specific transcription factors driving tissue-specific expression not identified
    • Functional significance of IAP retroviral insertion in Ren-2 not directly proven
  3. 1989 High

    The 2.5 Å crystal structure of recombinant human renin revealed a conserved aspartyl proteinase core with variable surface loops conferring substrate specificity, enabling rational inhibitor design and explaining renin's narrow substrate selectivity for angiotensinogen.

    Evidence X-ray crystallography with molecular dynamics refinement of recombinant human renin

    PMID:2493678

    Open questions at the time
    • Structure of renin bound to angiotensinogen not yet determined
    • Prosegment conformation and activation mechanism not resolved structurally
  4. 1990 High

    Transgenic expression of the mouse Ren-2 gene in rats caused severe hypertension despite low plasma active renin, demonstrating that extrarenal renin expression is sufficient to drive hypertension and establishing the concept of tissue-based renin-angiotensin systems.

    Evidence Transgenic rat generation (TGR(mREN2)27) with blood pressure measurement, renin activity assays, and subsequent vascular perfusion studies

    PMID:1592469 PMID:2181319

    Open questions at the time
    • Relative contribution of individual tissue sites (adrenal, vascular, brain) to hypertension not dissected
    • Mechanism of prorenin activation in peripheral tissues unclear
  5. 1992 High

    Identification of PC1 as the specific convertase that processes prorenin to active renin in a secretory-granule-dependent manner resolved the long-standing question of how prorenin activation is compartmentalized, explaining why non-granulated cells secrete only prorenin.

    Evidence Vaccinia virus co-expression of renin with PC1, PC2, or furin in granulated (GH4) versus non-granulated (CHO, BSC-40) cells; biosynthetic labeling and immunoprecipitation

    PMID:1597471

    Open questions at the time
    • Whether PC1 is the sole physiological convertase in juxtaglomerular cells in vivo not confirmed
    • Sorting signals directing prorenin to secretory granules not mapped
  6. 2001 High

    Discovery that Ren-1c transcription requires an Abd-B HOX·PBX·PREP1 ternary complex at a proximal promoter element identified the first transcription factor complex controlling renin gene expression, answering how cell-type-specific transcription is achieved.

    Evidence EMSA, point mutagenesis of HOX/PBX binding sites, transfection-based transcription assays, and in vivo DNA binding studies in As4.1 juxtaglomerular cells

    PMID:11432851

    Open questions at the time
    • Whether this HOX·PBX·PREP1 mechanism operates at the human REN promoter not shown
    • Upstream signals that regulate HOX factor expression in juxtaglomerular cells unknown
  7. 2002 High

    Cloning of the (pro)renin receptor revealed that renin binding to a dedicated receptor both enhances catalytic efficiency fourfold and triggers angiotensin II–independent ERK1/2 signaling, establishing a new signaling paradigm beyond renin's classical enzymatic role.

    Evidence Expression cloning, stable transfection, binding kinetics, angiotensinogen conversion assay, and MAP kinase phosphorylation in mesangial cells; confocal co-localization

    PMID:12045255

    Open questions at the time
    • Structural basis of receptor-mediated catalytic enhancement not resolved
    • Physiological significance of receptor signaling in vivo not established at this point
  8. 2003 High

    Mapping of the prosegment 'gate' and 'handle' regions revealed the molecular mechanism of reversible non-proteolytic prorenin activation, explaining how prorenin can gain enzymatic activity without prosegment cleavage.

    Evidence Region-specific antibody-based activation/inactivation assays at 4°C with equilibrium binding analysis; structure-guided antigen design

    PMID:12684512

    Open questions at the time
    • No high-resolution structure of the prorenin-to-renin conformational transition
    • Whether non-proteolytic activation occurs physiologically at the (pro)renin receptor not directly shown
  9. 2006 High

    Demonstration that prorenin activates p38 MAPK/HSP27 signaling and drives actin cytoskeletal remodeling via the (pro)renin receptor, independently of angiotensin II, extended receptor signaling beyond ERK1/2 to a second major MAPK cascade with transcriptional consequences.

    Evidence p38 MAPK phosphorylation assays with SB203580 inhibitor, microarray profiling (~260 regulated genes), 2D proteomics, and immunoblotting in neonatal rat cardiomyocytes; pharmacological exclusion of AT1/AT2 and renin catalytic activity

    PMID:16940215 PMID:18212269

    Open questions at the time
    • In vivo relevance of (pro)renin receptor–p38 signaling in cardiac pathology not demonstrated
    • Downstream transcriptional effectors mediating cytoskeletal remodeling not identified
  10. 2005 High

    Identification of biallelic REN loss-of-function mutations as a cause of autosomal recessive renal tubular dysgenesis established that renin is essential for human proximal tubular development.

    Evidence Linkage analysis and candidate gene sequencing in 9 families with 11 affected individuals showing fetal anuria and absent proximal tubular differentiation

    PMID:16116425

    Open questions at the time
    • Mechanism by which angiotensin II drives tubular differentiation not elucidated
    • Whether renin has angiotensin-independent developmental roles not addressed
  11. 2009 High

    Discovery that dominant signal-peptide mutations in REN impair ER translocation, trigger the unfolded protein response, and cause progressive juxtaglomerular cell loss established the pathogenic mechanism of autosomal dominant tubulointerstitial kidney disease (ADTKD-REN).

    Evidence Linkage analysis, in vitro translation and ER translocation assays, ER stress marker analysis, cell growth assays, and kidney biopsy immunohistochemistry

    PMID:19664745

    Open questions at the time
    • Whether ER stress is the sole mechanism or whether loss of renin secretion also contributes not fully separated
    • Animal model recapitulating ADTKD-REN not yet reported
  12. 2010 High

    Crystal structures of angiotensinogen alone (2.1 Å) and in complex with renin (4.4 Å) revealed that the angiotensin cleavage site is normally buried and requires a redox-sensitive conformational change for renin access, explaining why the oxidized form of angiotensinogen is the preferred substrate.

    Evidence X-ray crystallography of angiotensinogen and angiotensinogen–renin complex; redox state quantification in normal and pre-eclamptic plasma

    PMID:20927107

    Open questions at the time
    • High-resolution structure of the complex not available (4.4 Å limits mechanistic detail)
    • Whether redox regulation of angiotensinogen is a physiological control point in vivo requires further testing
  13. 2020 High

    A large international cohort study defined three distinct ADTKD-REN subtypes based on mutation location (signal peptide, prosegment, mature renin), each with a different trafficking defect and clinical trajectory, unifying the genotype-phenotype spectrum of dominant renin mutations.

    Evidence Genotyping of 111 individuals from 30 families, cellular trafficking studies, secretion assays, signal peptide hydrophobicity analysis, survival analysis

    PMID:32750457

    Open questions at the time
    • Therapeutic strategies to mitigate ER stress or restore trafficking not tested
    • Whether modifier genes influence ADTKD-REN progression not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of (pro)renin receptor–mediated signaling, the in vivo physiological relevance of angiotensin II–independent (pro)renin receptor pathways, and the cell-biological mechanisms linking ER-trapped renin mutants to progressive kidney fibrosis.
  • No high-resolution structure of renin bound to the (pro)renin receptor
  • In vivo genetic models dissecting receptor signaling from catalytic function lacking
  • Mechanism of fibrosis downstream of ER stress in ADTKD-REN not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016787 hydrolase activity 4
Localization
GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
AGTATP6AP2HOXA10HOXD10PBX1PCSK1PREP1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 The primary structure of human renin precursor was deduced from cDNA sequencing, revealing a 406-amino acid preprorenin with a 20-amino acid pre-segment and 46-amino acid pro-segment, with high sequence homology to mouse renin and structural similarity to aspartyl proteinases. cDNA library screening, nucleotide sequencing, sequence homology analysis Proceedings of the National Academy of Sciences of the United States of America High 6324167
1984 The human renin gene spans ~12 kb of DNA, contains 9 exons (encoding a 403-amino acid preprorenin) interrupted by 8 introns, with a TATA box promoter and glucocorticoid-response-like elements ~200–300 bp upstream; its structure is evolutionarily related to pepsinogen, and there is a single copy in the human genome. Genomic DNA cloning, restriction mapping, DNA sequencing, hybridization with mouse renin cDNA and synthetic oligonucleotide probes Proceedings of the National Academy of Sciences of the United States of America High 6089171 6391881
1984 Mouse Ren-1 and Ren-2 genes exhibit markedly different tissue-specific expression patterns despite conserved proximal promoter elements; a repetitive DNA element (IAP retroviral provirus) and sequence differences ~150 bp upstream of the transcription start site distinguish the Ren-2 copy, and tissue-specific utilization of homologous transcription start sites underlies their differential expression. Genomic sequencing, S1 nuclease analysis, comparative 5'-flanking region analysis, Northern blot Molecular and cellular biology High 6392850
1984 A complete intra-cisternal A particle (IAP) retroviral genome (MIARN) was identified within the Ren-2 locus of DBA/2 mice, flanking the 5' LTR with a phenylalanine tRNA-complementary sequence required for minus-strand synthesis initiation; this retroviral association may contribute to the high expression of Ren-2. Complete nucleotide sequencing of IAP genome, structural analysis of LTRs and tRNA binding site Nucleic acids research Medium 6095203
1985 Both Ren-1 and Ren-2 loci are expressed in the kidney of two-gene mouse strains at approximately equal mRNA levels, demonstrated using reverse transcriptase-mediated primer extension assays exploiting base sequence differences between the two highly homologous transcripts. Reverse transcriptase-mediated primer extension with dideoxynucleotide discrimination, oligonucleotide primer-based allele-specific assay Proceedings of the National Academy of Sciences of the United States of America High 3898081
1988 Physical mapping by pulsed-field gel electrophoresis revealed that mouse Ren-1 and Ren-2 are separated by ~20 kb of DNA, transcribed in the same orientation, with Ren-2 upstream of Ren-1, within a ~120 kb genomic region on chromosome 1. Pulsed-field gel electrophoresis, restriction mapping Nucleic acids research High 2833727
1989 The complete nucleotide sequence of mouse Ren-1d was determined; all three renin genes (Ren-1c, Ren-1d, Ren-2d) span ~9.6 kb with 9 exons and 8 introns, with significant sequence differences in their 5'-flanking regions that likely underlie differential regulation. Complete genomic DNA sequencing, comparative sequence analysis of 5'-flanking regions Gene High 2691339
1989 Expression of the DBA/2J Ren-2 transgene in mice was restricted to the X-zone of the adrenal gland (rather than cycling between X-zone and zona fasciculata as in native DBA/2 mice), demonstrating that cell-specific adrenal expression of Ren-2 is mediated in trans by at least one additional locus not present in the host genome. Transgenic mouse generation, tissue expression analysis, hormonal control experiments, genetic crosses The EMBO journal High 2480233
1989 The two Ren-1 alleles (Ren-1c and Ren-1d) exhibit characteristic, allele-specific expression patterns in adrenal gland, testis, and sex accessory gland tissue that are regulated by closely associated cis-acting sequences, as demonstrated by allele-specific dideoxynucleotide primer extension assays and genetic analysis. Allele-specific dideoxynucleotide primer extension assay, genetic analysis of one- vs two-gene mouse strains The Journal of biological chemistry High 2677011
1989 The crystal structure of recombinant human renin was determined at 2.5 Å resolution, revealing that renin is an aspartyl proteinase with a highly conserved structural core and active site compared to other aspartyl proteinases, but with variable surface loops that confer substrate specificity; this structural knowledge enabled rational inhibitor design. X-ray crystallography with molecular dynamics refinement Science High 2493678
1990 Introduction of the mouse Ren-2 renin gene into the rat genome caused severe fulminant hypertension without overexpression of active renin in the kidney or elevated plasma active renin, establishing that extrarenal expression of a renin gene is sufficient to cause severe hypertension and providing a model of low-renin hypertension. Transgenic rat generation, blood pressure measurement, renin activity assays Nature High 2181319
1990 Mouse Ren-2 prorenin (42 kDa, pI 6.5) was purified from transfected Chinese hamster ovary cells; amino-terminal sequencing confirmed the predicted prorenin sequence from the Ren-2 preprorenin cDNA, establishing that CHO cells secrete the correctly processed prorenin form. CHO cell transfection, multi-step chromatographic purification (DEAE-Toyopearl, Blue-Toyopearl, isoelectric focusing), SDS-PAGE, amino-terminal sequencing Journal of biochemistry High 2202716
1991 Substrate (angiotensinogen) paucity in Mus, consistent with first-order kinetics, phenotypically inhibits the renin-angiotensin system and was a prerequisite for the evolutionary emergence of enhanced Ren-2 expression in the submandibular gland; intravenous angiotensinogen injection markedly raised blood pressure, demonstrating that substrate limitation normally constrains renin activity. Comparative physiological experiments, intravenous substrate injection, blood pressure measurement across Mus strains General and comparative endocrinology Medium 1916217
1992 The mouse Ren-2 transgene is expressed in vascular (mesenteric and aortic) tissue of transgenic rats, leading to substantially increased vascular angiotensin I and II formation (measured by HPLC and RIA from perfused hindquarters); bilateral nephrectomy abolished angiotensin release in controls but not transgenic rats, establishing that vascular Ren-2 expression drives local angiotensin formation independent of kidney renin. Isolated perfused hindquarter preparation, HPLC, radioimmunoassay, RNase protection assay, Northern blot, bilateral nephrectomy Hypertension High 1592469
1992 Prorenin is markedly elevated in plasma of Ren-2 transgenic rats despite suppressed active renin and angiotensin levels; hypertension is driven by angiotensin II and is extremely sensitive to ACE inhibitor (captopril) treatment, and sodium depletion normalizes blood pressure, implicating a volume-dependent/adrenal renin-angiotensin component. Transgenic rat model, blood pressure monitoring, ACE inhibitor treatment, sodium depletion protocol, prorenin/renin assays Kidney international. Supplement Medium 1630068
1992 Prorenin is converted to active renin by the convertase PC1 in a cell-type-specific manner requiring secretory granules (demonstrated in GH4 somatomammotroph cells), but not by PC2 or furin, and not in cells lacking granules (CHO, BSC-40 cells); this establishes the intracellular compartment as a critical determinant of prorenin processing. Vaccinia virus expression system, biosynthetic labeling, cell-type comparison (GH4 vs CHO/BSC-40), immunoprecipitation The Journal of biological chemistry High 1597471
1993 Renin mRNA is expressed in multiple human tissues (kidney, adrenal gland, placenta, saphenous vein) as quantified by competitive PCR using a deletion-mutant internal standard; kidney has the highest renin mRNA concentration, followed by adrenal, placenta, and vein. Reverse transcription-PCR, competitive quantitative PCR with internal deletion-mutant standard The Journal of clinical investigation High 8387539
1993 The Ren-2 transgene in TGR(mREN2)27 rats is expressed in cardiovascular-regulatory organs (adrenal, kidney, brain) before hypertension develops; hypertension is associated with decreased plasma angiotensin I and near-undetectable angiotensin-(1-7), and is mediated by the renin-angiotensin system since ACE inhibition and AT1 blockade normalize blood pressure, with nitric oxide contributing more in transgenic than normotensive rats. Transgenic rat model, plasma angiotensin peptide measurement, lisinopril/losartan pharmacological intervention, L-NMMA injection, RNase protection assay The American journal of physiology High 8184972 8238495
1994 In Ren-2 transgenic hypertensive rats, central (intracerebroventricular) administration of angiotensin II or angiotensin-(1-7) increases local vasopressin (AVP) release from paraventricular and supraoptic nuclei in control but not transgenic rats, demonstrating that insertion of the mouse renin gene alters the brain angiotensin-vasopressin axis; transgenic rats showed 22-fold higher AVP in the dorsal lower brain stem. Brain microdialysis, intracerebroventricular infusion, radioimmunoassay of AVP and angiotensin peptides The American journal of physiology Medium 8092324
1994 In Ren-2 transgenic rat coronary arteries, hypertension selectively abolishes endothelium-dependent contractions in response to L-NAME (NOS inhibition), while endothelium-dependent relaxations to acetylcholine and smooth muscle function remain intact, indicating a selective impairment of EDNO-dependent contractile tone. Isolated coronary artery myograph/organ chamber preparation, isometric tension recording, pharmacological dissection with L-NAME, SQ30741 Circulation Medium 8205692
1995 Tubuloglomerular feedback (TGF) responses in Ren-2 transgenic hypertensive rats are enhanced and ~84% dependent on angiotensin II acting via AT1 receptors (blocked by L-158,809), with only ~43% of the attenuation attributable to blood pressure reduction alone, establishing a direct role for locally generated angiotensin II in sensitizing the TGF mechanism. Stop-flow pressure micropuncture, AT1 receptor antagonist administration, mechanical renal arterial pressure reduction The American journal of physiology Medium 7771510
1996 Targeted inactivation of the mouse Ren-2 gene showed that mice lacking Ren-2 are viable and normotensive, with increased active renin and decreased prorenin in plasma; the Ren-1d gene alone is sufficient to regulate normal blood pressure, demonstrating that Ren-2 is functionally redundant for blood pressure control despite differing tissue expression. Gene targeting/knockout, blood pressure measurement, plasma renin and prorenin quantification, histopathological analysis Hypertension High 8952610
1998 In female Ren-2 transgenic rats, adrenal angiotensin II is significantly elevated compared to controls, while kidney angiotensin II is unchanged but angiotensin I and angiotensin-(1-7) are lower; cardiac angiotensin I, II, and angiotensin-(2-10) are reduced while angiotensin-(2-7) is increased. Tissue angiotensins cycle with estrous stage in both strains, establishing organ-specific angiotensin II generation patterns driven by the Ren-2 transgene. HPLC, radioimmunoassay of multiple angiotensin peptides from adrenal, kidney, and heart tissue Peptides Medium 9880073
1998 Concomitant with elevated adrenal renin activity in TGR(mREN2)27 rats, adrenocortical steroid production is elevated and aldosterone regulation is impaired; since kidney and plasma renin and angiotensins are low, these findings establish a functional role for the local adrenal renin-angiotensin system (driven by Ren-2) in controlling aldosterone production. Adrenal renin activity measurement, steroid and aldosterone assays, comparison with plasma/kidney renin levels in transgenic vs control rats Hormone and metabolic research Medium 9694562
1999 AT1 receptor binding is significantly increased in glomeruli, proximal tubules, and inner stripe of outer medulla of Ren-2 transgenic hypertensive rats (but not AT2 receptors), mainly in vascular smooth muscle of intrarenal vessels, juxtaglomerular apparatus, mesangial cells, and proximal tubular cells; AT1 blockade with losartan markedly reduced mean arterial pressure and increased renal blood flow in transgenic but not control rats, establishing that upregulated intrarenal AT1 receptors mediate the renal hemodynamic effects of elevated angiotensin II. In vitro autoradiography of renal AT1/AT2 receptors, immunohistochemistry, renal hemodynamics measurement, AT1/AT2 receptor blockade Hypertension High 9931128
1999 Ren-2 hypertensive transgenic rats exhibit exaggerated renal vascular responsiveness specifically to angiotensin II (but not to norepinephrine or vasodilators), with intrarenal angiotensin II causing larger decreases in renal blood flow than in normotensive controls, establishing a selective enhancement of angiotensin II-mediated renal vasoconstriction. Intravenous and intrarenal arterial angiotensin II administration, renal blood flow measurement, pharmacological comparison with norepinephrine, bradykinin, and acetylcholine The American journal of physiology Medium 9950963
2000 BAC transgenesis of a 145 kb region encompassing both Ren-1d and Ren-2 loci completely rescued juxtaglomerular cell granulation and macula densa morphology in Ren-1d-null mice; homologous recombination inserting an IRES-β-geo marker into Ren-1d confirmed that juxtaglomerular cells express Ren-1d throughout development even without granulation, and that Ren-2 overexpression cannot functionally compensate for loss of Ren-1d, establishing primary structural differences between the two isoforms as responsible for differential granulation. BAC transgenesis, homologous recombination in E. coli (piggy-BAC), backcross genetic complementation, lacZ reporter expression, histological analysis The Journal of biological chemistry High 10995772
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 consensus sequence (TAATAAATCAA); Abd-B HOX members (HOXD10, HOXA10, HOXA9, HOXB9, HOXC9) bind this element with or without PBX1b, and point mutations in either the HOX or PBX half-site dramatically decreased Ren-1c transcriptional activity; PBX1b, PREP1, and HOX form a ternary complex on the PPE both in vivo and in vitro. Electrophoretic mobility shift assay, in vitro binding assays, point mutagenesis, transfection-based transcriptional activity assays, in vivo DNA binding studies in As4.1 cells The Journal of biological chemistry High 11432851
2002 Renin and prorenin binding to the cloned (pro)renin receptor (a 350-amino acid single transmembrane domain protein) increases the catalytic efficiency of angiotensin I generation from angiotensinogen fourfold and induces intracellular signaling (phosphorylation of serine/tyrosine residues and ERK1/2 activation) independently of angiotensin II; the receptor is localized by confocal microscopy to glomerular mesangium and subendothelium of coronary and kidney arteries, co-localizing with renin. Expression cloning, stable transfection, specific binding assay, angiotensinogen conversion kinetics, MAP kinase phosphorylation assay, confocal microscopy The Journal of clinical investigation High 12045255
2003 Human prorenin has a 'gate' region (T7PFKR10P) and 'handle' region (I11PFLKR15P) in the prosegment that are critical for its non-proteolytic activation; antibodies targeting the handle region (anti-11/26) non-proteolytically activate 90% of prorenin at 4°C, and acid-activated prorenin exposes both regions for antibody binding; handle- and gate-region antibodies prevent re-inactivation, defining the molecular mechanism of reversible prorenin activation. Antibody-based non-proteolytic activation assay, acid-activation/re-inactivation experiments, equilibrium dissociation constant determination, tertiary structure-guided antigen design The Journal of biological chemistry High 12684512
2004 Renin-expressing cells in the brain were identified using an eGFP reporter transgene driven by the mouse renin promoter; eGFP-positive cells were found in cerebellum, hippocampus, dorsal motor nucleus of the vagus, inferior olivary nucleus, reticular formation, rostral ventrolateral medulla, central nucleus of the amygdala, lateral parabrachial nucleus, mesencephalic trigeminal nucleus, bed nucleus of stria terminalis, and subfornical organ; co-labeling confirmed these cells are predominantly neuronal. eGFP reporter transgenic mouse, fluorescence microscopy, co-immunolabeling with neuron- and glia-specific antisera Physiological genomics High 14625376
2005 Loss-of-function mutations in renin (REN), angiotensinogen, ACE, or angiotensin II type 1 receptor cause autosomal recessive renal tubular dysgenesis, characterized by fetal anuria and absence of differentiated proximal tubules; this establishes that REN activity and the renin-angiotensin system are essential for human renal tubular development. Linkage analysis, candidate gene sequencing, homozygosity/compound heterozygosity mapping in 9 families with 11 affected individuals Nature genetics High 16116425
2006 Prorenin and renin binding to the (pro)renin receptor in human monocytes (U937 cells) induces long-lasting ERK1/2 phosphorylation independently of angiotensin II (persisting with AT1 and AT2 receptor blockade), via MEK1/2-dependent signaling; this signaling is distinct from angiotensin II-ERK signaling (not involving EGF receptor transactivation). Aliskiren (direct renin inhibitor) does not block (pro)renin receptor binding or ERK1/2 activation. Immunoprecipitation, Western blot for phospho-ERK1/2, receptor binding with 125I-labeled renin/prorenin, AT1/AT2 blockade, MEK inhibitor, FACS analysis Hypertension High 18212269
2006 Prorenin activates p38 MAPK and phosphorylates HSP27 in neonatal rat cardiomyocytes through the (pro)renin receptor, independently of angiotensin II (not blocked by aliskiren or AT1 antagonist eprosartan); this leads to transcriptional regulation of ~260 genes including those involved in actin filament dynamics and results in actin cytoskeleton remodeling. p38 MAPK phosphorylation assay, SB203580 (p38 inhibitor) blocking experiment, microarray gene expression profiling (4800 genes), quantitative RT-PCR, 2D proteomics, immunoblotting Hypertension High 16940215
2007 ACE2 is the primary enzyme responsible for cardiac angiotensin-(1-7) generation from angiotensin II in hypertrophic hearts of Ren-2 hypertensive rats; ACE2 inhibition (MLN-4760) reduced cardiac angiotensin-(1-7) production by 83% in hypertensive but had no significant effect in normotensive hearts, demonstrating a compensatory upregulation of cardiac ACE2 in hypertension. Langendorff isolated heart preparation, HPLC-RIA angiotensin peptide measurement, pharmacological ACE2 inhibition, ACE2 activity assay, Western blot for ACE2 protein American journal of physiology. Heart and circulatory physiology High 17308000
2009 Dominant mutations in the signal sequence of human renin (p.Leu16del, p.Leu16Arg) reduce signal peptide hydrophobicity, impair ER translocation and processing of preprorenin, resulting in reduced or abolished prorenin/renin biosynthesis and secretion; cells expressing p.Leu16del show activated ER stress, unfolded protein response, and reduced growth rate, causing progressive juxtaglomerular cell loss and autosomal dominant kidney disease. Linkage analysis, candidate gene sequencing, transfection studies, in vitro translation, ER translocation assay, ER stress markers (Western blot), cell growth assay, kidney biopsy immunohistochemistry American journal of human genetics High 19664745
2010 The crystal structure of human angiotensinogen at 2.1 Å reveals that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail; a 4.4 Å structure of the angiotensinogen-renin complex reveals the conformational rearrangement (linked by a conserved disulphide bridge) required for renin to access and cleave the substrate. The oxidized (sulphydryl-bridged) form of angiotensinogen preferentially interacts with receptor-bound renin, and the reduced:oxidized ratio is ~40:60 in circulation, rising in pre-eclampsia. X-ray crystallography (2.1 Å angiotensinogen alone; 4.4 Å complex with renin), redox state analysis of circulating angiotensinogen, pre-eclampsia patient samples Nature High 20927107
2011 miR-663 and miR-181a bind to the 3'-UTR of the REN mRNA and regulate renin mRNA levels in human kidney (HEK293) cells, as demonstrated by luciferase reporter gene experiments; in hypertensive human kidneys, two miRNAs are downregulated, potentially explaining elevated intrarenal renin mRNA. Microarray transcriptomics, quantitative RT-PCR validation, luciferase reporter assay with REN 3'-UTR in HEK293 cells, miRNA transfection Hypertension Medium 22042811
2020 An international cohort study of 111 individuals from 30 families with ADTKD-REN defined three pathophysiologically distinct subtypes based on mutation location: (1) signal peptide mutations reduce hydrophobicity required for ER recognition/translocation, leading to aberrant cytoplasmic delivery of preprorenin; (2) prosegment mutations cause prorenin/renin deposition in the ER-Golgi intermediate compartment with decreased secretion; (3) mature renin mutations cause mutant prorenin deposition in the ER (similar to ADTKD-UMOD), with slowest progression to end-stage kidney disease. International cohort clinical study, genotyping of 30 families, signal peptide hydrophobicity analysis, cellular trafficking studies (ER-Golgi localization), secretion assays, survival analysis Kidney international High 32750457

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2002 Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. The Journal of clinical investigation 1101 12045255
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1990 Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 840 2181319
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2010 Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nature cell biology 286 20081843
1983 Cloning and sequence analysis of cDNA for human renin precursor. Proceedings of the National Academy of Sciences of the United States of America 285 6324167
1993 Gene expression of the renin-angiotensin system in human tissues. Quantitative analysis by the polymerase chain reaction. The Journal of clinical investigation 224 8387539
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
1992 The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors. The Journal of biological chemistry 216 1320019
1971 Kinetics of the human renin and human substrate reaction. Cardiovascular research 206 4322712
2006 Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II. Hypertension (Dallas, Tex. : 1979) 198 16940215
2008 Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Archives of general psychiatry 194 18519826
2011 Gene expression profiling reveals renin mRNA overexpression in human hypertensive kidneys and a role for microRNAs. Hypertension (Dallas, Tex. : 1979) 193 22042811
1989 Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution. Science (New York, N.Y.) 191 2493678
2008 Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. Hypertension (Dallas, Tex. : 1979) 186 18212269
2005 Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nature genetics 182 16116425
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2010 A redox switch in angiotensinogen modulates angiotensin release. Nature 155 20927107
1992 Cloning and characterization of a human angiotensin II type 1 receptor. Biochemical and biophysical research communications 155 1567413
1992 Proprotein conversion is determined by a multiplicity of factors including convertase processing, substrate specificity, and intracellular environment. Cell type-specific processing of human prorenin by the convertase PC1. The Journal of biological chemistry 155 1597471
2003 Human prorenin has "gate and handle" regions for its non-proteolytic activation. The Journal of biological chemistry 154 12684512
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 151 15249678
1984 Human renin gene: structure and sequence analysis. Proceedings of the National Academy of Sciences of the United States of America 147 6089171
2015 Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor. The Journal of biological chemistry 146 26420482
2006 The DNA sequence and biological annotation of human chromosome 1. Nature 144 16710414
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2004 Localization of renin expressing cells in the brain, by use of a REN-eGFP transgenic model. Physiological genomics 66 14625376
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2007 Retinal dysfunction in diabetic ren-2 rats is ameliorated by treatment with valsartan but not atenolol. Investigative ophthalmology & visual science 48 17251496
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2007 Valsartan but not atenolol improves vascular pathology in diabetic Ren-2 rat retina. American journal of hypertension 46 17386351
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1997 Cardiovascular end-organ damage in Ren-2 transgenic rats compared to spontaneously hypertensive rats. Journal of molecular medicine (Berlin, Germany) 46 9181479
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1994 Estrogen augments the contribution of nitric oxide to blood pressure regulation in transgenic hypertensive rats expressing the mouse Ren-2 gene. American journal of hypertension 42 7946157
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 41 33478552
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 40 25969338
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2006 Spectroscopic characterization of the tumor antigen NY-REN-21 and identification of heterodimer formation with SCAND1. Biochemical and biophysical research communications 33 16540086
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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
2020 An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes. Kidney international 31 32750457
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
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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
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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
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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
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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
2000 An organic solvent resistant tyrosinase from Streptomyces sp. REN-21: purification and characterization. Bioscience, biotechnology, and biochemistry 21 10737179
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
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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
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 17 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
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1990 Purification of mouse Ren 2 prorenin produced in Chinese hamster ovary cells. Journal of biochemistry 17 2202716
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.) 16 33233046
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
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
2020 Untargeted metabolomic study on the insomnia effect of Suan-Zao-Ren decoction in the rat serum and brain using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry combined with data processing analysis. Journal of separation science 14 32072764
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
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