Role of PCSK1N and GPR83 in salt resistance

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Previous studies from our laboratory show that in mice increased expression/function of the orphan receptor GPR83 is associated with salt resistance. GPR83 is expressed in proximal and distal convoluted tubules of the mouse kidney. Global deletion or renal‐specific silencing of the GPR83 gene increases systolic blood pressure (SBP) and increased G protein‐coupled receptor kinase type 4 (GRK4) expression in the kidney. Recent evidence indicated that peptides derived from the Proprotein Convertase Subtilisin/Kexin Type 1 Inhibitor (PCSK1N) may be the endogenous ligands of GPR83. We hypothesized that these peptides are implicated in the regulation of blood pressure. Renal specific siRNA‐mediated silencing of PCSK1N in mice resulted in an increase in SBP (130±4 vs control wild‐type 100±1 mmHg, n=3/group; P<0.05); this was associated with decreased urinary Na+ excretion (P<0.05) and decreased renal cortex expression of GPR83, but increased NHE3 and Na+/K+‐ATPase expressions (P<0.05 all). The peptides PEN (proline, glutamic acid, and asparagine) and SAAS (serine, alanine, alanine, and serine) are derived from enzymatic breakdown of Pro‐SAAS. Renal restricted infusion of PEN (1 μg/day; 7 days) did not affect SBP, slightly decreased Na+ excretion and increased GPR83, GRK4, and NHE3 expressions (P<0.05 all) but did not affect Na+/K+‐ATPase expression. By contrast, renal‐restricted infusion of SAAS (1 μg/day; 7 days) in mice decreased SBP (82± vs 100± mmHg; P<0.05), Na+ excretion did not change but decreased the renal cortex expression of GRK4, GPR83, NHE3 and Na+/K+‐ATPAse (P<0.05 all). Furthermore, PCSK1N expression was increased by a high salt diet (4%NaCl) in non‐transgenic mice but was decreased in the salt‐sensitive GRK4 486V mice on the same diet. Our result suggested that Pro‐SAAS peptides may be involved in the development of salt sensitivity through gene‐gene interactions among PCSK1N, GPR83, and GRK4.Support or Funding InformationThis work was supported by NIH grant t R01DK039308 (P.A.J.);NIH grant R37HL023081(P.A.J.); NIH grant P01HL074940 (P.A.J.); NIH grant P01HL068686 (P.A.J.); NIH grant R01HL092196 (P.A.J., I.A.); NIH grant R01DK09098 (I.A.)