(Pro)renin receptor mediates albumin-induced cellular responses: role of site-1 protease-derived soluble (pro)renin receptor in renal epithelial cells

Abstract

Proteinuria is a characteristic of chronic kidney disease and also a causative factor that promotes the disease progression, in part, via activation of the intrarenal renin-angiotensin system (RAS). (Pro)renin receptor (PRR), a newly discovered component of the RAS, binds renin and (pro)renin to promote angiotensin I generation. The present study was performed to test the role of soluble PRR (sPRR) in albumin overload-induced responses in cultured human renal proximal tubular cell line human kidney 2 (HK-2) cells. Bovine serum albmuin (BSA) treatment for 24 h at 20 mg/ml induced renin activity and inflammation, both of which were attenuated by a PRR decoy inhibitor PRO20. BSA treatment induced a more than fivefold increase in medium sPRR due to enhanced cleavage of PRR. Surprisingly, this cleavage event was unaffected by inhibition of furin or a disintegrin and metalloproteinase 19. Screening for a novel cleavage enzyme led to the identification of site-1 protease (S1P). Inhibition of S1P with PF-429242 or siRNA remarkably suppressed BSA-induced sPRR production, renin activity, and inflammatory response. Administration of a recombinant sPRR, termed sPRR-His, reversed the effects of S1P inhibition. In HK-2 cells overexpressing PRR, mutagenesis of the S1P, but not furin cleavage site, reduced sPRR levels. Together, these results suggest that PRR mediates albumin-induced cellular responses through S1P-derived sPRR.

Enzymatic sources and physio-pathological functions of soluble (pro)renin receptor

“…Moreover, mutagenesis in cleavage site of the S1P, not furin decreases sPRR production in cultured renal cells overexpressing PRR. These results suggest that S1P plays a dominant role in the generation of sPRR and this S1P-derived sPRR mediates albumin-induced cellular responses [35]. However, our results show that furin inhibition has no effect on the size shift of sPRR as reported by Nagagawa et al [34].…”

Soluble (pro)renin receptor treats metabolic syndrome in mice with diet-induced obesity via interaction with PPARγ

“…Earlier studies showed that the PRR cleavage process depended on furin or ADAM19 (10,22). However, recent studies by Nakagawa et al (23) and our group (24), in which different approaches were used, consistently identified site-1 protease (S1P) as the predominant or only source of sPRR production. This finding allowed evaluation of the involvement of S1P-derived endogenous sPRR in the current experimental model.…”

Site-1 protease–derived soluble (pro)renin receptor targets vasopressin receptor 2 to enhance urine concentrating capability

“…Earlier studies showed that the cleavage process depended on furin or ADAM19 (17,18). However, recent studies by Nakagawa et al (19) and our laboratory (20) using different approaches consistently demonstrate that site-1 protease (S1P) functions as a predominant source of sPRR production. In the present study, we attempted to define the role of S1P-derived sPRR in regulation of fluid homeostasis and to study the underlying mechanism involving V 2 R regulation.…”

“…Recent reports from our group and others have identified S1P as a predominant protease responsible for the generation of sPRR (19,20). Therefore, we examined the role of S1P-derived sPRR in mediating AVP upregulation of V 2 R expression in primary rat IMCD cells.…”

“…S1P has recently been identified as a predominant protease responsible for generation of sPRR (19,20). In the present study, we employed a S1P inhibitor and RT S1P-KO model to test the potential role of endogenous sPRR in regulation of fluid homeostasis.…”