Renal protein phosphatase 2A activity and spontaneous hypertension in rats

The impaired renal paracrine function of dopamine in spontaneously hyperten sive rats (SHR) is caused by hyperphosphorylation and desensitization of th e renal D-1 dopamine receptor. Protein phosphatase 2A (PP2A) is critical in the regulation of G-protein-coupled receptor function. To determine whethe r PP2A expression and activity in the kidney are differentially regulated i n genetic hypertension, well examined the effects of a D-1-like agonist, fe noldopam, in renal cortical tubules and immortalized renal proximal tubule cells from normotensive Wistar-Kyoto rats (WKY) and SHR. In cortical tubule s and immortalized proximal tubule cells, PP2A expression and activities we re greater in cytosol than in membrane fractions in both WKY and SHR. Altho ugh PP2A expressions were similar in WKY and SHR, basal PP2A activity was g reater in immortalized proximal tubule cells of SHR than WKY, In immortaliz ed proximal tubule cells of WKY, fenoldopam increased membrane PP2A activit y and expression of the regulatory subunit PP2A-B56 alpha, effects that wer e blocked by the D-1-like antagonist SCH23390. Fenoldopam had no effect on cytosolic PP,, activity but decreased PP2A-B56 alpha expression. In contras t, in immortalized proximal tubule cells of SHR, fenoldopam decreased PP2A activity in both membranes and cytosol but predominantly in the membrane fr action, without affecting PP2A-B56 alpha expression; this effect was blocke d by the D-1-Iike antagonist SCH23390. We conclude that renal PP2A activity and expression are differentially regulated in WKY and SHR by D-1-like rec eptors. A failure of D-1-like agonists to increase PP2A activity in proxima l tubule membranes may be a cause of the increased phosphorylation of the D -1 receptor in the SHR.