Dopamine 1 Receptor, G sα , and Na + -H + Exchanger Interactions in the Kidney in Hypertension

Author:

Xu Jing1,Li Xiao Xi1,Albrecht Frederick E.1,Hopfer Ulrich1,Carey Robert M.1,Jose Pedro A.1

Affiliation:

1. From the Departments of Pediatrics (J.X., X.X.L., F.E.A., P.A.J.) and Physiology and Biophysics (F.E.A., P.A.J.), Georgetown University Medical Center, Washington, DC; Department of Physiology, Case Western Reserve School of Medicine, Cleveland, Ohio (U.H.); and Department of Medicine, University of Virginia Health Sciences Center, Charlottesville (R.M.C.).

Abstract

Abstract —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 , or effector proteins. The coupling of the D 1 receptor to G and NHE3 was studied in renal brush border membranes (BBM), devoid of cytoplasmic second messengers. D 1 receptor, G , and NHE3 expressions were similar in SHR and their normotensive controls, Wistar-Kyoto rats (WKY). Guanosine-5′- O -(3-thiotriphosphate) (GTPγS) decreased NHE activity and increased NHE3 linked with G similarly in WKY and SHR, indicating normal G and NHE3 regulation in SHR. However, D 1 agonists increased NHE3 linked with G 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, GTPγS 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 /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 /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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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