Activation of D4 Dopamine Receptor Decreases Angiotensin II Type 1 Receptor Expression in Rat Renal Proximal Tubule Cells

The dopaminergic and renin–angiotensin systems interact to regulate blood pressure. Disruption of the D 4 dopamine receptor gene in mice produces hypertension that is associated with increased renal angiotensin type 1 (AT 1 ) receptor expression. We hypothesize that the D 4 receptor can inhibit AT 1 receptor expression and function in renal proximal tubule cells from Wistar–Kyoto (WKY) rats, but the D 4 receptor regulation of AT 1 receptor is aberrant in renal proximal tubule cells from spontaneously hypertensive rats (SHRs). The D 4 receptor agonist, PD168077, decreased AT 1 receptor protein expression in a time- and concentration-dependent manner in WKY cells. By contrast, in SHR cells, PD168077 increased AT 1 receptor protein expression. The inhibitory effect of D 4 receptor on AT 1 receptor expression in WKY cells was blocked by a calcium channel blocker, nicardipine, or calcium-free medium, indicating that calcium is involved in the D 4 receptor–mediated signaling pathway. Angiotensin II increased Na + -K + ATPase activity in WKY cells. Pretreatment with PD168077 decreased the stimulatory effect of angiotensin II on Na + -K + ATPase activity in WKY cells. In SHR cells, the inhibitory effect of D 4 receptor on angiotensin II–mediated stimulation of Na + -K + ATPase activity was aberrant; pretreatment with PD168077 augmented the stimulatory effect of AT 1 receptor on Na + -K + ATPase activity in SHR cells. This was confirmed in vivo; pretreatment with PD128077 for 1 week augmented the antihypertensive and natriuretic effect of losartan in SHRs but not in WKY rats. We suggest that an aberrant interaction between D 4 and AT 1 receptors may play a role in the abnormal regulation of sodium excretion in hypertension.