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.