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Angiotensin II AT1 and AT2 receptors are differentially dysfunctional to regulate Na‐K‐ATPase Activity in the Proximal Tubules of Spontaneously Hypertensive (SHR) rats.

Higher antinatriuretic response to angiotensin II (ang II) is believed to contribute to the pathogenesis of hypertension; however, the mechanism is not understood. We have shown that activation of ang II AT1 receptors stimulates NKA activity while the activation of AT2 receptors inhibits the enzyme activity. In the present study, the expression and function of AT1 and AT2 receptors to regulate Na, K‐ATPase (NKA) activity were investigated in the isolated proximal tubules (PTs) of SHR and Wistar‐Kyoto rats (12 wk). Western blot revealed that AT1 receptor expression was increased in the PTs of SHR compared to WKY rats, while the expression of AT2 receptor was similar in both rat strains. CGP42112A (100 nM), an AT2 receptor agonist significantly inhibited the NKA activity in the PTs of WKY rats, but did not affect the enzyme activity in SHR. The NKA activity inhibition by CGP was attenuated by the AT2 receptor antagonist PD123319 (1μM), NO synthase inhibitor, L‐NAME and guanylate cyclase inhibitor ODQ, indicating the involvement of AT2 receptor via NO/cGMP pathway in the NKA activity inhibition in WKY rats. On the other hand, Ang II in a concentration dependent manner (100 −0.1pM) significantly stimulated the NKA activity in the PTs of the SHR but not in WKY rats. Ang II‐mediated stimulation was attenuated by AT1 receptor antagonist losartan, suggesting the involvement of AT1 receptor. We conclude that inability of AT2 receptor to inhibit NKA and enhanced AT1 receptor‐mediated stimulation of NKA activity may contribute to increase in the renal sodium retention and the pathogenesis of hypertension in SHR (supported by NIH‐DK61578).