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

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 o...