Dopamine, receptor, Gsα, and Na+-H+ exchanger interactions in the kidney in hypertension

The ability of dopamine(1) (D-1) receptors to inhibit luminal Na+-H+ exchanger (NHE) activity in renal proximal tubules and induce a natriuresis is impaired in spontaneously hypertensive rats (SHR). However, it is not clear whether the defect is at the level of the D-1 receptor, G(s alpha), or effector proteins. The coupling of the D-1 receptor to G(s alpha) and NHE3 was studied in renal brush border membranes (BBM), devoid of cytoplasmic second messengers. D-1 receptor, G(s alpha), and NHE3 expressions were similar in SHR and their normotensive controls, Wistar-Kyoto rats (WKY). Guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S) decreased NHE activity and increased NHE3 linked with G(s alpha) similarly in WKY and SHR, indicating normal G(s alpha) and NHE3 regulation in SHR. However, D-1 agonists increased NHE3 linked with G(s alpha) in WKY but not in SHR, and the inhibitory effects of D-1 agonists on NHE activity were less in SHR than in WKY. Moreover, GTP gamma S enhanced the inhibitory effect of D-1 agonist on NHE activity in WKY but not in SHR, suggesting an uncoupling of the D-1 receptor from G(s alpha)/NHE3 in SHR. Similar results were obtained with the use of immortalized renal proximal tubule cells from WKY and SHR.We conclude that the defective D-1 receptor function in renal proximal tubules in SHR is proximal to G(s alpha)/effectors and presumably at the receptor level. The mechanism(s) responsible for the uncoupling of the D-1 receptor from G proteins remains to be determined. Because the primary structure of the D-1 receptor is not different between normotensive and hypertensive rats, differences in D-1 receptor posttranslational modification are possible.