Human Prorenin Structure Sheds Light on a Novel Mechanism of Its Autoinhibition and on Its Non-Proteolytic Activation by the (Pro)renin Receptor

Morales, Renaud; Watier, Yves; Böcskei, Zsolt

doi:10.1016/j.jmb.2012.05.003

Cited by 24 publications

(24 citation statements)

References 27 publications

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“…Such a role has also been demonstrated with regard to prorenin binding to the (pro)renin receptor. 40,41 Glycosylation is less likely to contribute to this phenomenon, since Ren2 prorenin is non-glycosylated (unlike the recombinant human renin and prorenin preparations applied in the present study) and yet it behaved in exactly the same manner as prorenin in the human and mouse studies: it remained undetectable in urine, despite excessive rises and high blood pressure-induced reninuria and albuminuria.…”

Section: Perspectivementioning

confidence: 68%

On the Origin of Urinary Renin

et al. 2016

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Urinary angiotensinogen excretion parallels albumin excretion, which is not the case for renin, while renin’s precursor, prorenin, is undetectable in urine. We hypothesized that renin and prorenin, given their smaller size, are filtered through the glomerulus in larger amounts than albumin and angiotensinogen, and that differences in excretion rate are due to a difference in reabsorption in the proximal tubule. To address this, we determined the glomerular sieving coefficient (GSC) of renin and prorenin, and measured urinary renin/prorenin 1) after inducing prorenin in Cyp1a1-Ren2 rats, and 2) in patients with Dent’s disease or Lowe syndrome, disorders characterized by defective proximal tubular reabsorption. GSCs followed molecular size (renin>prorenin>albumin). The induction of prorenin in rats resulted in a >300-fold increase in plasma prorenin and doubling of blood pressure, but did not lead to the appearance of prorenin in urine. It did cause parallel rises in urinary renin and albumin, which losartan but not hydralazine prevented. Defective proximal tubular reabsorption increased urinary renin and albumin 20-40-fold, and allowed prorenin detection in urine, at ≈50% of its levels in plasma. Taken together, these data indicate that circulating renin and prorenin are filtered into urine in larger amounts than albumin. All 3 proteins are subsequently reabsorbed in the proximal tubule. For prorenin such reabsorption is ≈100%. Minimal variation in tubular reabsorption (in the order of a few %) is sufficient to explain why urinary renin and albumin excretion do not correlate. Urinary renin does not reflect prorenin that is converted to renin in tubular fluid.

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Section: Perspectivementioning

confidence: 68%

On the Origin of Urinary Renin

et al. 2016

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“…The human renin gene spans 12 kb of DNA on chromosome 1 and contains 10 exons separated by 9 introns (124). The transcript encodes a protein with 406 amino acids, including a pre- and a pro-segment carrying 20-23 and 43-47 amino acids, respectively (8, 149, 243). Removal of the 23 amino acid residues from the C-terminus of pre-pro-renin generates pro-renin.…”

Section: Renin Genementioning

confidence: 99%

Classical Renin‐Angiotensin System in Kidney Physiology

Sparks

Crowley

Gurley

et al. 2014

Comprehensive Physiology

462

429

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The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardio-vascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the “classical” renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the “classical” renin-angiotensin system, with an emphasis on new developments and modern concepts.

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“…37 The transgenic rat (TGR(mREN2)27), harboring the mouse Ren 2 gene, shows fulminant hypertension without elevated circulating concentrations of renin. 38 The mechanisms of A B Figure 6.…”

Section: July 2014mentioning

confidence: 99%

Identification of Bona Fide Alternative Renin Transcripts Expressed Along Cortical Tubules and Potential Roles in Promoting Insulin Resistance In Vivo Without Significant Plasma Renin Activity Elevation

et al. 2014

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Abstract-Renin belongs to a family of aspartyl proteases and is the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II. Processing of renal renin has been extensively investigated in juxtaglomerular granular cells, in which prorenin and active renin are present in secretory condensed granules. Previous studies demonstrated alternative renin transcription in rat adrenal glands. Different studies reported novel intracellular forms of renin deduced from novel 5′ variants derived from renin mRNA in both mice and humans. Comprehensive detailed studies in genetically engineered mice showed that both a secreted and an intracellular form of renin plays divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system; however, the presence, regulation, and functions of these renin isoforms in kidney and adrenal gland are not fully understood in mice. To investigate the characteristics of renin isoforms in mice, we performed a systematic inventory of renin transcripts of mice with and without a duplication of the renin gene alternatively from previous studies. We discovered a novel isoform of renin of the Ren2 gene, which conserved functionally important residues of the prosegment and incomplete isoforms of the Ren1C/D gene lacking a pre-pro segment. In situ hybridization assays revealed alternative renin isoforms expressed along cortical tubules. Newly generated transgenic mice with systemic overexpression of alternative renin transcript showed enhanced local angiotensin II generation without elevation of plasma renin activity and systemic insulin resistance in vivo, providing new pathophysiological insights into insulin resistance exaggerated by bona fide renin isoform. Correspondence to Tomoaki Ishigami, Department of Medical Science and Cardio-Renal Medicine, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan. E-mail tommmish@hotmail.com Identification of Bona Fide Alternative Renin Transcripts Expressed Along Cortical Tubules and Potential Roles in Promoting Insulin Resistance In Vivo Without Significant Plasma Renin Activity ElevationTomoaki Ishigami, Tabito Kino,* Lin Chen,* Shintaro Minegishi, Naomi Araki, Masanari Umemura, Kaito Abe, Rie Sasaki, Hisako Yamana, Satoshi Umemura © 2014 American Heart Association, Inc. Materials and Methods Cloning and Identification of Alternative Renin Transcripts AnimalsAll animals were purchased from Oriental Yeast Company (Mihama, Chiba, Japan) and were housed and maintained under conditions approved by the Institution Animal Care and Use Committee of Yokohama City University. Rapid Amplification of cDNA Ends ProtocolTo investigate whether alternative renin expression is found in mouse adrenal glands, we performed 5′ rapid amplification of cDNA ends (RACE) analysis in adrenal tissue from 129 mice that endogenously have both Ren1D and Ren2 renin 6 and C57BL/6J mice with Ren1C renin. RNA was isolated from the mice with the use of Trizol reagent (Invitrogen, C...

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Human Prorenin Structure Sheds Light on a Novel Mechanism of Its Autoinhibition and on Its Non-Proteolytic Activation by the (Pro)renin Receptor

Cited by 24 publications

References 27 publications

On the Origin of Urinary Renin

On the Origin of Urinary Renin

Classical Renin‐Angiotensin System in Kidney Physiology

Identification of Bona Fide Alternative Renin Transcripts Expressed Along Cortical Tubules and Potential Roles in Promoting Insulin Resistance In Vivo Without Significant Plasma Renin Activity Elevation

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