LAUSR

Objectives: In the kidney, activation of the AT1 receptor increases renal sodium reabsorption, whereas the AT2 receptor produces the opposite effect. We hypothesized that the AT2 receptor regulates AT1 receptor expression and function in the kidney. Methods: Renal proximal tubule (RPT) cells from Wistar-Kyoto rats (WKY) were stimulated through AT2 receptors to observe AT1 expression. NO synthase pathway, Sp1 serine phosphorylation, Na +-K +-ATPase activity and AT1/AT2 receptors co-immunoprecipitation were used to study the interaction mechanism. Results: CGP42112, an AT2 receptor agonist, decreased AT1 receptor mRNA and protein expression. The inhibitory effect of the AT2 receptor on AT1 receptor expression was blocked by the AT2 receptor antagonist, PD123319, the NO synthase inhibitor L-NAME (10–4 M), or the NO-dependent soluble guanylate cyclase inhibitor ODQ (10–5 M), indicating that both NO and cGMP were involved in the signaling pathway. Furthermore, CGP42112 decreased Sp1 serine phosphorylation and reduced the binding of Sp1 to AT1 receptor DNA. Stimulation with Ang II enhanced Na+-K+-ATPase activity in RPT cells, which was prevented by pretreatment with CGP42112. The above-mentioned results were confirmed in RPT cells from AT2 receptor knockout mice; AT1 receptor expression and Ang II-stimulated Na+-K+-ATPase activity were greater in these cells than in RPT cells from wild-type mice. AT1/AT2 receptors colocalized and co-immunoprecipitated in RPT cells; short-term CGP42112 treatment increased AT1/AT2 receptor co-immunoprecipitation. Conclusion: These results indicate that the renal AT2 receptor, via NO/cGMP/Sp1 pathway, regulates AT1 receptor expression and function, which may be important in the regulation of sodium excretion and blood pressure.