D3 DOPAMINE RECEPTOR REGULATION OF D5 RECEPTOR EXPRESSION AND FUNCTION IN RENAL PROXIMAL TUBULE CELLS: PP.9.348

Abstract

Disruption of the D3 dopamine receptor gene in mice produces hypertension that is associated with a decreased ability to excrete an acute sodium load. The mechanism of the decreased ability of the D3 receptor knockout mice to excrete a sodium load is not known. However, D3 receptors, with or without interaction with D1 receptors, can inhibit sodium transporter/pump activities (NHE3, Na+-K+ ATPase). We have reported positive interactions between D3 and D1 receptors in renal proximal tubule (RPT) cells; stimulation of one receptor increases the expression and function of the other receptor. Because both D1 and D5 receptors belong to the D1-like receptor family, we presume that there is also an interaction between D3 and D5 receptors in RPT cells. We now report that a D3 receptor agonist, PD128907, increased the expression of D5 receptors in a concentration- (10–9–10–6 M) [control = 0.6±0.2, 10–7 M/24hrs PD128907 = 1.3±0.2 density units (DU); P < 0.01, n = 6] and time (2 hrs-30 hrs)-dependent (control = 0.6±0.1, 10–7 M/24hrs PD128907 = 1.3±0.2 DU; P < 0.01, n = 4) manner in RPT cells from Wistar-Kyoto (WKY) rats. The effect of PD128907 (10–7 M) was blocked by the D3 receptor antagonist, U99194A (10–5 M/24hrs) (control = 0.8±0.07, PD128907 = 1.5±0.1, U99194A = 0.8±0.09, PD128907 + U99194A = 0.8±0.08 DU, P < 0.01, n = 7). The stimulatory effect of the D3 receptor on D5 receptor expression was impaired in RPT cells from spontaneously hypertensive rats (SHRs) (D5 receptor protein: WKY: control = 1±0.05, PD128907 = 1.9±0.1; SHR: control = 0.7±0.05, PD128907 = 0.5±0.08 DU, n = 6). Stimulation of the D5 receptor in D5 receptor-transfected HEK 293 (D5-HEK293) cells inhibited Na+-K+ ATPase activity. Pretreatment with PD128907 (10–7 M) for 24 hours increased the D5 receptor expression and the D5 receptor-mediated inhibitory effect on Na+-K+ ATPase activity in D5-HEK293 cells (control = 0.15±0.006, fenoldopam alone = 0.12±0.01, PD128907 pretreatment + fenoldopam = 0.09± 0.007, n = 8). We suggest that D3 and D5 receptors positively interact with each other. Altered interaction between D3 and D5 receptors may play a role in the pathogenesis of hypertension.