Interaction of Angiotensin II Type 1 and D 5 Dopamine Receptors in Renal Proximal Tubule Cells

Abstract

Angiotensin II type 1 (AT 1 ) receptor and D 1 and D 3 dopamine receptors directly interact in renal proximal tubule (RPT) cells from normotensive Wistar-Kyoto rats (WKY). There is indirect evidence for a D 5 and AT 1 receptor interaction in WKY and spontaneously hypertensive rats (SHR). Therefore, we sought direct evidence of an interaction between AT 1 and D 5 receptors in RPT cells. D 5 and AT 1 receptors colocalized in WKY cells. Angiotensin II decreased D 5 receptors in WKY cells in a time- and concentration-dependent manner (EC 50 =2.7×10 −9 M; t 1/2 =4.9 hours), effects that were blocked by an AT 1 receptor antagonist (losartan). In SHR, angiotensin II (10 −8 M/24 hours) also decreased D 5 receptors (0.96±0.08 versus 0.72±0.08; n=12) and to the same degree as in WKY cells (1.44±0.07 versus 0.92±0.08). However, basal D 5 receptors were decreased in SHR RPT cells (SHR 0.96±0.08; WKY 1.44±0.07; n=12 per strain; P <0.05) and renal brush border membranes of SHR compared with WKY (SHR 0.54±0.16 versus WKY 1.46±0.10; n=5 per strain; P <0.05). Angiotensin II decreased AT 1 receptor expression in WKY (1.00±0.04 versus 0.72±0.08; n=8; P <0.05) but increased it in SHR (0.96±0.04 versus 1.32±0.08; n=8; P <0.05). AT 1 and D 5 receptors also interacted in vivo; renal D 5 receptor protein was higher in mice lacking the AT 1A receptor (AT 1A −/−; 1.61±0.31; n=6) than in wild-type littermates used as controls (AT 1A +/+; 0.81±0.08; n=6; P <0.05), and renal cortical AT 1 receptor protein was higher in D 5 receptor null mice than in wild-type littermates (1.18±0.08 versus 0.84±0.07; n=4; P <0.05). We conclude that D 5 and AT 1 receptors interact with each other. Altered interactions between AT 1 and dopamine receptors may play a role in the pathogenesis of hypertension.