Background The endothelin receptor B (ETBR) regulates blood pressure and water and electrolyte balance by engendenring natriuresis. In hypertensive states, the ETBR mediated diureis and natriuresis is impaired. However, the underlying mechanisms are not clear. G protein-coupled receptor kinase 4 (GRK4), whose gene locus 4p16.3 is linked to essential hypertension, cause sodium retention and increase blood pressure via impairment of renal dopamine receptor and enhancement of renin-angiotensin system functions. Due to the higher activity of GRK4 in kidney from spontaneously hypertensive rats (SHRs) and hypertensive patients, we hypothesise that GRK4 might be the cause of ETBR impairment in hypertension.
Method Experiments were carried out in male anaesthetic spontaneously hypertensive rats (SHR)and in normotensive Wistar-Kyoto (WKY) rats. The ETB receptor agonist, BQ-3020 (0.1, 0.5, 1.0 ug/kg/min) were infused via supra-renal artery at a rate of 0.04 ml/min for 40 min. The same experiments were conducted in GRK4 A142V and GRK4 Wild Type transgenic mice. The ETBR function were also checked in the wild-type and A142V transfected renal proximal tubule (RPT) cells from mice.
Results We found that diuresis and natriuresis of ETBR agonist, BQ3020, in Wistar-Kyoto (WKY) rats, which was impaired in SHRs. The GRK4 expression was higher in renal cortex from SHRs as compared with WKY rats. In GRK4 A142V transgenic mice, it resulted that ETBR-mediated diuresis and natriuresis was impaired compared with Wild type. In wild-type transfected cells, activation of ETBR inhibited Na+-K+-ATPase activity; while in A142V transfected cells, the inhibitory effect was lost. There are co-localization and co-immunoprecipitation between ETBR and GRK4 in RPT cells. The linkage of ETBR/GRK4 was higher in wilde-type cells than in A142V cells. Similar phenomenon was found in the kidney from WKY and SHRs, SHRs had higher ETBR/GRK4 linkage, accompanied with higher ETBR phosphorylation, which might account for the impaired ETBR function in hypertension.
Conclusion This study provides a mechanism by which GRK4, via regulation of renal ETBR function, participates in the pathogenesis of hypertension.
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