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(Hypertension. 2000;36:1053.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Renal Protein Phosphatase 2A Activity and Spontaneous Hypertension in Rats

Peiying Yu; Laureano D. Asico; Gilbert M. Eisner; Ulrich Hopfer; Robin A. Felder; Pedro A. Jose

From the Departments of Pediatrics (P.Y., L.D.A., P.A.J.) and Physiology and Biophysics (P.A.J.), Georgetown University School of Medicine, Washington, DC; the Department of Internal Medicine (G.M.E.), Washington Hospital Center, Washington, DC; the Department of Physiology (U.H.), Case Western Reserve School of Medicine, Cleveland, Ohio; and the Department of Pathology and Medical Automation Research Center (R.A.F.), Charlottesville, Va.

Correspondence to Peiying Yu, MD, Department of Pediatrics, PHC-2, Georgetown University Medical Center, 3800 Reservoir Rd NW, Washington, DC 20007. E-mail yup{at}gunet.georgetown.edu

Abstract—The impaired renal paracrine function of dopamine in spontaneously hypertensive rats (SHR) is caused by hyperphosphorylation and desensitization of the renal D₁ dopamine receptor. Protein phosphatase 2A (PP_2A) is critical in the regulation of G-protein–coupled receptor function. To determine whether PP_2A expression and activity in the kidney are differentially regulated in genetic hypertension, we examined the effects of a D₁-like agonist, fenoldopam, in renal cortical tubules and immortalized renal proximal tubule cells from normotensive Wistar-Kyoto rats (WKY) and SHR. In cortical tubules and immortalized proximal tubule cells, PP_2A expression and activities were greater in cytosol than in membrane fractions in both WKY and SHR. Although PP_2A expressions were similar in WKY and SHR, basal PP_2A activity was greater in immortalized proximal tubule cells of SHR than WKY. In immortalized proximal tubule cells of WKY, fenoldopam increased membrane PP_2A activity and expression of the regulatory subunit PP_2A-B56, effects that were blocked by the D₁-like antagonist SCH23390. Fenoldopam had no effect on cytosolic PP_2A activity but decreased PP_2A-B56 expression. In contrast, in immortalized proximal tubule cells of SHR, fenoldopam decreased PP_2A activity in both membranes and cytosol but predominantly in the membrane fraction, without affecting PP_2A-B56 expression; this effect was blocked by the D₁-like antagonist SCH23390. We conclude that renal PP_2A activity and expression are differentially regulated in WKY and SHR by D₁-like receptors. A failure of D₁-like agonists to increase PP_2A activity in proximal tubule membranes may be a cause of the increased phosphorylation of the D₁ receptor in the SHR.

Key Words: hypertension, genetic • receptors, dopamine • dopamine • hypertension, essential • phosphatase