Role of G-protein-coupled receptor kinase 4 on the dysfunction of renal Mas receptor in hypertension

TL;DR

This study shows that GRK4 causes dysfunction in the Mas receptor in the kidneys of hypertensive rats, suggesting GRK4 could be a new target for hypertension treatment.

Contribution

The novel finding is that GRK4 regulates the renal Mas receptor and contributes to hypertension pathogenesis.

Findings

GRK4 increases phosphorylation and impairs function of the renal Mas receptor in hypertension.

GRK4 silencing improves Mas receptor function and reduces hypertension-related kidney dysfunction.

Targeting GRK4 in the kidney may be a viable therapeutic strategy for hypertension.

Abstract

The angiotensin converting enzyme 2/angiotensin-(1–7)/Mas receptor axis plays an important role in the regulation of blood pressure. G protein-coupled receptor kinase 4 (GRK4) has attracted more attentions by modulating G protein-coupled receptors and blood pressure. However, it remains unknown whether renal Mas receptor is regulated by GRK4 and its role in the pathogenesis of hypertension. Compared with Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs) exhibited impaired Mas receptor-mediated diuresis and natriuresis, which was accompanied with increased phosphorylation levels of Mas receptors. Similarly, the phosphorylation of renal Mas receptor was increased and its-induced renal effects were decreased in human (h) GRK4γ 142V transgenic mice relative to wild-type littermates. There was a colocalization and a direct interaction of renal Mas receptor and GRK4, which were increased in SHRs and confirmed by rigid protein–protein docking. In vitro studies found that treatment with the Mas receptor agonist AVE0991 inhibited Na+-K+-ATPase activity in WKY renal proximal tubule (RPT) cells, which was failed in SHR cells. GRK4 silencing decreased the phosphorylation of Mas receptor and improved the impaired Mas receptor-mediated inhibition of Na+-K+-ATPase activity in SHR RPT cells. Further study showed that ultrasound-targeted microbubble destruction-targeted renal GRK4 depletion decreased Mas receptor phosphorylation and improved its-induced diuresis and natriuresis in SHRs. These suggest that GRK4 contributes to increased renal Mas receptor phosphorylation and dysfunction in hypertension, indicating that targeting GRK4 may be a viable therapeutic approach for hypertension.

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