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

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

  • Am J Physiol Cell Physiol. 2017 Dec 1;313(6):C632-C643. doi: 10.1152/ajpcell.00006.2017.
Hui Fang 1 Chuanming Xu 1 2 Aihua Lu 1 Chang-Jiang Zou 2 Shiying Xie 1 Yanting Chen 1 Li Zhou 1 Mi Liu 1 Lei Wang 1 Weidong Wang 1 Tianxin Yang 1 2
Affiliations

Affiliations

  • 1 Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China.
  • 2 Department of Internal Medicine, University of Utah School of Medicine and Veterans Affairs Medical Center , Salt Lake City, Utah.
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.

Keywords

albumin; pro(renin) receptor; renal proximal tubular cell renin activity; renin-angiotensin system.

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