Cathepsin B Is a Prorenin Processing Enzyme

Neves, Francisco A. R.; Duncan, Keith G.; Baxter, John D.

doi:10.1161/01.hyp.27.3.514

Cited by 66 publications

(46 citation statements)

References 27 publications

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“…About 80% of intracellular renin has little or no enzymatic activity and is called inactive renin or prorenin (2). Inactive renin can be converted into the active form through limited proteolysis at physiological pH by tissue proteases such as trypsin and kallikreins (3,4), but probably by cathepsin B in vivo (5).…”

Section: Introductionmentioning

confidence: 99%

Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

Andrade

Casarini

Schor

et al. 2002

Braz J Med Biol Res

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Renin is an enzyme involved in the stepwise generation of angiotensin II. Juxtaglomerular cells are the main source of plasma renin, but renin activity has been detected in other cell types. In the present study we evaluated the presence of renin mRNA in adult male Wistar rat and mouse (C-57 Black/6) mesangial cells (MC) and their ability to process, store and release both the active and inactive forms of the enzyme. Active renin and total renin content obtained after trypsin treatment were estimated by angiotensinogen consumption analyzed by SDS-PAGE electrophoresis and quantified by angiotensin I generation by HPLC. Renin mRNA, detected by RT-PCR, was present in both rat and mouse MC under basal conditions. Active renin was significantly higher (P<0.05) in the cell lysate (43.5 ± 5.7 ng h -1 10 6 cells) than in the culture medium (12.5 ± 2.5 ng h -1 10 6 cells). Inactive prorenin content was similar for the intra-and extracellular compartments (9.7 ± 3.1 and 3.9 ± 0.9 ng h -1 10 6 cells). Free active renin was the predominant form found in both cell compartments. These results indicate that MC in culture are able to synthesize and translate renin mRNA probably as inactive prorenin which is mostly processed to active renin inside the cell. MC secrete both forms of the enzyme but at a lower level compared with intracellular content, suggesting that the main role of renin synthesized by MC may be the intracellular generation of angiotensin II.

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Section: Introductionmentioning

confidence: 99%

Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

Andrade

Casarini

Schor

et al. 2002

Braz J Med Biol Res

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“…However, many tissues have enzymes other than ACE that are capable of converting angiotensin I into Ang II (Figure 4). For instance, the heart expresses tonins, cathepsins, chymases and trypsin that can synthesize Ang II from Ang I [Hollenberg et al 1998;Neves et al 1996;Kramkowski et al 2006]. As a result; attempts to inhibit the RAS could fail to induce the desired effects on vasoconstriction and on renal sodium excretion.…”

Section: Aceis Arbs and Direct Renin Inhibitors: Differential Featuresmentioning

confidence: 99%

Direct renin inhibition: extricating facts from façades

Juncos¹

2013

Therapeutic Advances in Cardiovascular Disease

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Abstract:The renin-angiotensin system (RAS) affects vascular tone, cardiac output and kidney function. By these means the RAS plays a key role in the pathogenesis of arterial hypertension. As a result, RAS inhibition is highly effective not only in lowering blood pressure but also in reducing kidney disease progression (particularly when associated with proteinuria) and cardiovascular events.Among RAS blocking agents, direct renin inhibitors have shown not only excellent efficacy in hypertension control but also pharmacologic tolerance that is comparable with other reninangiotensin suppressors. Indeed, aliskiren, the only direct renin inhibitor available is effective in controlling blood pressure as monotherapy or in combination with other antihypertensive drugs, irrespective of patient's age, ethnicity or sex. It is also effective in patients with metabolic syndrome, obesity and diabetes. Long-term studies comparing 'hard endpoints' of aliskiren therapy versus treatment with other RAS inhibitors, including cardiac and kidney protection, are currently ongoing. Combined with other antihypertensive agents, aliskiren not only improves their hypotensive response but may also lessen the adverse effects of other drugs. In high-risk patients, however, precautions should be taken when combining two or more renin-angiotensin inhibiting agents, as tissue perfusion may be highly renin-dependent in these patients and serious adverse side effects could take place.

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“…It was known for some time that a number of enzymes exhibited the capability of processing prorenin to active renin in vitro, e.g., cathepsins B, D, and G, tissue kallikrein, convertases, trypsin, mouse submandibular gland prorenin converting enzyme, plasmin, pepsin, and others (2,6,10,14,17,18). However, there were issues of proteolysis causing degradation or issues regarding the colocalization of the enzymes with renin in vivo, which lead to uncertainty about their roles.…”

mentioning

confidence: 99%

“…Neves et al (18) showed that cotransfection of cathepsin B and human preprorenin expression vectors into secretory granule-containing rat GH4C1 cells resulted in enhanced generation of secretable active renin relative to the preprorenin vector alone. This suggests that cathepsin B could localize to the appropriate cellular compartment to effect correct processing in an intact cell.…”

mentioning

confidence: 99%

Twists and turns in the search for the elusive renin processing enzyme: focus on “Cathepsin B is not the processing enzyme for mouse prorenin”

Gross

Gomez

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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HAVING WORKED FOR MANY YEARS on relatively basic questions germane to the venerable renin-angiotensin system, we were musing with some fascination recently on the continuing evolution of our understanding of the system. In particular, we were taking note of the considerable amount of dogma, with varying levels of verification associated with the system, as well as the almost continuous infusion of remarkable new twists and turns that seem to mark the passing of time. We were also struck by the existence of a surprising number of unresolved core issues.Research from Reudelhuber's laboratory (13a) has a direct bearing on one of these core issues, a central question that has eluded a completely satisfactory explanation for some time: namely, the identity of the prorenin processing enzyme (PPE) that generates active renin in the juxtaglomerular cell of the kidney. This is not a trivial question. For, while there may be local activation of renin at various tissue-specific sites, the experimental evidence suggests that the preponderant source of systemically circulating active renin is the kidney. As the authors correctly point out, unequivocal identification of the PPE might thus provide a new pharmaceutical target to inhibit this critical rate-limiting step of the renin-angiotensin system, thus providing a potential novel therapy for hypertension and cardiovascular disease.Their article is of significance, not for its positive identification of a novel PPE, but rather, for its rigorous exclusion of a longtime favorite candidate for the PPE, cathepsin B, at least in the specific case of mice. Satisfactory resolution of the issue has been complicated by a number of factors, including the fact that multiple enzymes appear to be able to generate "active" renin in vitro, different NH 2 -terminal sequences have been identified for the presumptive mature renal renin of human, mouse, and rat origin, and the in vitro cell systems in hand are, for the most part, nonoptimal or nonrepresentative of the renal site in question.It was known for some time that a number of enzymes exhibited the capability of processing prorenin to active renin in vitro, e.g., cathepsins B, D, and G, tissue kallikrein, convertases, trypsin, mouse submandibular gland prorenin converting enzyme, plasmin, pepsin, and others (2,6,10,14,17,18). However, there were issues of proteolysis causing degradation or issues regarding the colocalization of the enzymes with renin in vivo, which lead to uncertainty about their roles. Cathepsin B has enjoyed preferential, if not quite dogmatic, status as the PPE candidate of choice for a number of reasons.It was noted early on by Taugner and Hackenthal (24) that the secretory pathway in the renal juxtaglomerular cell of rats appeared to involve granules that had the characteristics of modified lysosomes. Not surprisingly, cathepsin B, along with a number of other lysosomal enzyme candidates, was shown to exhibit cellular and organelle colocalization with prorenin.A series of straightforward studies undertaken by Hsueh...

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Cathepsin B Is a Prorenin Processing Enzyme

Cited by 66 publications

References 27 publications

Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

Direct renin inhibition: extricating facts from façades

Twists and turns in the search for the elusive renin processing enzyme: focus on “Cathepsin B is not the processing enzyme for mouse prorenin”

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