Kir7.1 knockdown and inhibition alter renal electrolyte handling but not the development of hypertension in Dahl salt-sensitive rats.

Abstract

High K⁺ supplementation is correlated with a lower risk of the composite of death, major cardiovascular events, and ameliorated blood pressure, but the exact mechanisms have not been established. Inwardly rectifying K⁺ (K_ir) channels expressed in the basolateral membrane of the distal nephron play an essential role in maintaining electrolyte homeostasis. Mutations in this channel family have been shown to result in strong disturbances in electrolyte homeostasis, among other symptoms. K_ir7.1 is a member of the ATP-regulated subfamily of K_ir channels. However, its role in renal ion transport and its effect on blood pressure have yet to be established. Our results indicate the localization of K_ir7.1 to the basolateral membrane of aldosterone-sensitive distal nephron cells. To examine the physiological implications of K_ir7.1, we generated a knockout of K_ir7.1 (Kcnj13) in Dahl salt-sensitive (SS) rats and deployed chronic infusion of a specific K_ir7.1 inhibitor, ML418, in the wild-type Dahl SS strain. Knockout of Kcnj13 (Kcnj13^-/-) resulted in embryonic lethality. Heterozygous Kcnj13^+/- rats revealed an increase in K⁺ excretion on a normal-salt diet but did not exhibit a difference in blood pressure development or plasma electrolytes after 3 wk of a high-salt diet. Wild-type Dahl SS rats exhibited increased renal K_ir7.1 expression when dietary K⁺ was increased. K⁺ supplementation also demonstrated that Kcnj13^+/- rats excreted more K⁺ on normal salt. The development of hypertension was not different when rats were challenged with high salt for 3 wk, although Kcnj13^+/- rats excrete less Na⁺. Interestingly, chronic infusion of ML418 significantly increased Na⁺ and Cl^- excretion after 14 days of high salt but did not alter salt-induced hypertension development. Here, we found that reduction of K_ir7.1 function, either through genetic ablation or pharmacological inhibition, can influence renal electrolyte excretion but not to a sufficient degree to impact the development of SS hypertension.NEW & NOTEWORTHY To investigate the role of the K_ir7.1 channel in salt-sensitive hypertension, its function was examined using complementary genetic and pharmacological approaches. The results revealed that although reducing K_ir7.1 expression had some impact on maintaining K⁺ and Na⁺ balance, it did not lead to a significant change in the development or magnitude of salt-induced hypertension. Hence, it is probable that K_ir7.1 works in conjunction with other basolateral K⁺ channels to fine-tune membrane potential.