Dopamine1 Receptor, Gsa, and Na-H Exchanger Interactions in the Kidney in Hypertension

The ability of dopamine1 (D1) 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 D1 receptor, Gsa, or effector proteins. The coupling of the D1 receptor to Gsa and NHE3 was studied in renal brush border membranes (BBM), devoid of cytoplasmic second messengers. D1 receptor, Gsa, and NHE3 expressions were similar in SHR and their normotensive controls, Wistar-Kyoto rats (WKY). Guanosine-59-O(3-thiotriphosphate) (GTPgS) decreased NHE activity and increased NHE3 linked with Gsa similarly in WKY and SHR, indicating normal Gsa and NHE3 regulation in SHR. However, D1 agonists increased NHE3 linked with Gsa in WKY but not in SHR, and the inhibitory effects of D1 agonists on NHE activity were less in SHR than in WKY. Moreover, GTPgS enhanced the inhibitory effect of D1 agonist on NHE activity in WKY but not in SHR, suggesting an uncoupling of the D1 receptor from Gsa /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 D1 receptor function in renal proximal tubules in SHR is proximal to Gsa /effectors and presumably at the receptor level. The mechanism(s) responsible for the uncoupling of the D1 receptor from G proteins remains to be determined. Because the primary structure of the D1 receptor is not different between normotensive and hypertensive rats, differences in D1 receptor posttranslational modification are possible. (Hypertension. 2000;36:395-399.)