Angiotensin II Type 2 Receptor–Mediated Inhibition of NaCl Absorption Is Blunted in Thick Ascending Limbs From Dahl Salt-Sensitive Rats

Abstract

NO reduces NaCl absorption by thick ascending limbs (TALs) by inhibiting the Na/K/2Cl cotransporter (NKCC2). We have shown that NO-induced inhibition of Na transport is reduced in Dahl salt-sensitive rat (SS) TALs. Angiotensin II increases NO production in TALs via angiotensin II type 2 receptor (AT₂R). It is unknown whether AT₂Rs regulate TAL NaCl absorption and whether this effect is reduced in SS rats. We hypothesized that AT₂R activation decreases TAL Na transport via NO, and this effect is blunted in SS rats. In the presence of angiotensin II type 1 receptor antagonist losartan, AT₂R activation with angiotensin II inhibited NKCC2 activity by 32±7% (P<0.03). AT₂R antagonist PD-123319 abolished the effect of angiotensin II. Activation with the AT₂R-selective agonist CGP42112A (10 nmol/L) decreased NKCC2 activity by 29±6% (P<0.03). The effect of CGP42112A on NKCC2 activity was blocked by PD-123319 and by NO synthase inhibitor N^G-nitro-l-arginine methyl ester. In Dahl salt-resistant rat TALs, 1 nmol/L of CGP42112A decreased NKCC2 activity by 23±4% (P<0.01). In SS TALs, it had no effect. TAL AT₂R mRNA did not differ in SS versus salt-resistant rats. We conclude the following: (1) TAL AT₂R activation decreases Na absorption; (2) this effect is mediated by AT₂R-induced stimulation of NO; (3) AT₂R-induced reduction of NKCC2 activity is blunted in SS rats; and (4) defects in AT₂R/NO signaling rather than decreased AT₂R expression likely account for the blunted effect in SS TALs. Impaired AT₂R-mediated signaling in TALs could contribute to the Na retention associated with salt-sensitive hypertension.