Soluble (Pro)Renin Receptor as a Negative Regulator of NCC (Na ⁺ -Cl – Cotransporter) Activity

NCC (Na + -Cl − cotransporter), uniquely located at the distal convoluted tubule (DCT), is the target of thiazide diuretics and critically involved in renal handling of both Na + and K + . However, the mechanism of how NCC activity is regulated remains incompletely understood. Here, we report a novel role of PRR ([pro]renin receptor) and its cleavage product sPRR (soluble PRR) via S1P (site-1 protease) as negative regulators of NCC during high-salt or high K + loading. Under basal condition, mice with DCT-specific deletion of PRR (DCT PRR KO) exhibited modest hypertension associated with reduced urinary Na + , K + , and Cl − excretion due to increased NCC activity. Following a high-salt diet, DCT PRR KO mice exhibited a ≈25 mm Hg increase of mean arterial pressure contrasting to salt resistance in the floxed controls. The null mice also exhibited impaired kaliuresis and hyperkalemia after high K + intake. This phenotype was recapitulated by treatment of C57/BL6 mice with S1P inhibitor PF429242. In cultured Flp-In T-REx 293 NCC cells, S1P-derived sPRR directly dephosphorylated NCC via activation of AT1R (angiotensin II receptor type 1). Taken together, the present study has demonstrated that S1P-derived sPRR via AT1R negatively regulates NCC activity in the DCT to render salt resistance and to promote K + excretion.