Inhibition of angiotensin type 1 receptor impairs renal ability of K conservation in response to K restriction.

Abstract

We have previously demonstrated that ANG II inhibits ROMK-like small-conductance K channels (SK) in the cortical collecting duct from rats on a K-deficient diet (KD) (35). In the present study, we examined the role of angiotensin type 1 receptor (AT(1)R) in mediating the effect of K restriction on K secretion. We confirmed the previous finding that K restriction increased the superoxide anion level, c-Src expression, and the phosphorylation of both p38 and extracellular signal-regulated kinase mitogen-activated protein kinase (MAPK) in renal cortex and outer medulla. However, the effect of K restriction on superoxide anion generation, c-Src expression, and MAPK phosphorylation was significantly attenuated in rats receiving losartan, an inhibitor of AT(1)R. In contrast, losartan treatment had no effect on superoxide anion level, c-Src expression, and MAPK phosphorylation in animals on a normal K diet (NK). K restriction decreased SK channel activity and increased the tyrosine phosphorylation of ROMK. However, inhibiting AT(1)R abolished the effect of K restriction on SK channels and tyrosine phosphorylation of ROMK channels. The notion that AT(1)R is involved in regulating renal K excretion was also supported by the experiments with metabolic cages showing that losartan treatment significantly enhanced urinary K loss in rats on a KD diet while it had no effect in animals on a NK diet. Consequently, losartan-treated animals had severe hypokalemia in response to K restriction compared with rats without losartan intake. We conclude that AT(1)R is involved in mediating the effect of K restriction on superoxide generation, c-Src, and MAPK and that inhibiting AT(1)R impairs renal ability of K conservation in response to K depletion.