Abstract 13013: Grk4-mediated Adiponectin Receptor-1 Phosphorylative Desensitization as a Novel Mechanism of Reduced Renal Sodium Excretion in Hypertension

Abstract

Introduction: Hypertensive patients have impaired sodium excretion. However, the mechanisms are incompletely understood. There is interaction between kidney and adipose tissue. Whether and how adiponectin, one of adipokines, contributes to impaired sodium excretion in hypertension has not been previously investigated. Hypothesis: Adiponectin promotes natriuresis and diuresis and their impairment is involved in hypertension. Methods: We used Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), GRK4g142A>V transgenic mice to test the natriuresis-effect of adiponectin through intrarenal arterial infusion. Renal proximal tubule (RPT) cells, adiponectin knock out (Adipo-/-) mice, mutant plasmid were used. Results: We demonstrate that sodium excretion was reduced in Adipo-/- mice. The intrarenal arterial infusion of adiponectin induced natriuresis and diuresis in WKY rats, which was impaired in SHRs. Adiponectin inhibited Na+-K+-ATPase activity in RPT cells from WKY rats but not from SHRs. Increased adiponectin receptor phosphorylation and subsequent uncoupling from Gai, rather than altered adiponectin receptor expression, were responsible for the loss of adiponectin-mediated inhibition of RPT Na+-K+-ATPase activity, impaired natriuresis and diuresis in SHRs. Mutation of the AdipoR1 phosphorylation site restored its linkage to Gai and the adiponectin-mediated inhibition of Na+-K+-ATPase activity in RPT cells from SHRs. Finally, we identified G protein-coupled receptor kinase 4 (GRK4) as the cause of adiponectin receptor hyper-phosphorylation. GRK4g142A>V transgenic mice replicated the abnormal adiponectin function in SHRs, whereas down-regulation of GRK4 by renal-ultrasound directed siRNA restored the adiponectin-mediated sodium excretion and reduced the blood pressure in SHRs. Conclusions: The stimulatory effect of adiponectin on sodium excretion is impaired in hypertension, which is attributable to increased renal GRK4 expression and subsequent adiponectin receptor hyper-phosphorylation. Targeting GRK4/adiponectin receptor/Gai may restore the impaired adiponectin-mediated sodium excretion in hypertension, thus representing a novel strategy against hypertension.