Jin Yan, Wang Yan, Wang Zhi-Jian, Lin Dao-Hong, Wang Wen-Hui
Department of Medical Genetics, Harbin Medical University, Harbin, China.
Am J Physiol Renal Physiol. 2009 May;296(5):F1179-84. doi: 10.1152/ajprenal.90725.2008. Epub 2009 Feb 11.
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.
我们之前已经证明，血管紧张素II（ANG II）可抑制低钾饮食（KD）大鼠皮质集合管中的ROMK样小电导钾通道（SK）（35）。在本研究中，我们研究了1型血管紧张素受体（AT(1)R）在介导钾限制对钾分泌影响中的作用。我们证实了之前的发现，即钾限制会增加肾皮质和外髓中的超氧阴离子水平、c-Src表达以及p38和细胞外信号调节激酶丝裂原活化蛋白激酶（MAPK）的磷酸化。然而，在接受AT(1)R抑制剂氯沙坦的大鼠中，钾限制对超氧阴离子生成、c-Src表达和MAPK磷酸化的影响显著减弱。相比之下，氯沙坦治疗对正常钾饮食（NK）动物的超氧阴离子水平、c-Src表达和MAPK磷酸化没有影响。钾限制降低了SK通道活性并增加了ROMK的酪氨酸磷酸化。然而，抑制AT(1)R消除了钾限制对SK通道和ROMK通道酪氨酸磷酸化的影响。代谢笼实验也支持了AT(1)R参与调节肾脏钾排泄的观点，该实验表明氯沙坦治疗显著增加了KD饮食大鼠的尿钾流失，而对NK饮食动物没有影响。因此，与未摄入氯沙坦的大鼠相比，氯沙坦治疗的动物在钾限制时出现严重低钾血症。我们得出结论，AT(1)R参与介导钾限制对超氧生成、c-Src和MAPK的影响，并且抑制AT(1)R会损害肾脏在钾缺乏时保留钾的能力。
