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

Abstract

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...

Classical Renin‐Angiotensin System in Kidney Physiology

“…The correct sorting of pro-renin to the regulated secretory pathway depends on the presence of a paired basic amino acid site in the pro-renin molecule, which serves as a protease-processing site. As cathepsins are co-localized with pro-renin in the secretory granules, it was suggested that these proteases might be responsible for the conversion of pro-renin to renin (113). However, renin processing was not impaired in cathepsin B deficient mice suggesting that cathepsin B is not essential for renin processing (239).…”

Protein Kinase G Is Involved in Acute but Not in Long-Term Regulation of Renin Secretion

“…A final proteolytic cleavage gives rise to mature renin, a protein with a molecular mass of around 36 kDa, which is then stored in intracellular vesicles until the cell obtains a release signal (Yokosawa et al, 1980). The underlying mechanisms of these processes as well as the identity of the protease responsible for renin activation still remain unclear (Gross et al, 2010).…”

Transgenic Mice Overexpressing Human Alpha-1 Antitrypsin Exhibit Low Blood Pressure and Altered Epithelial Transport Mechanisms in the Inactive and Active Cycles

“…The conversion of inactive prorenin to active renin occurs in secretory granules after proteolytic processing. A few studies report that cathepsin B is the human prorenin processing enzyme ( Wang et al, 1991 ; Shinagawa et al, 1995 ; Neves et al, 1996 ) while other studies report that it is not the processing enzyme for prorenin in mice ( Gross et al, 2010 ; Mercure et al, 2010 ). This indicates that species differences exist.…”