Activation of Kir4.1/Kir5.1 contributes to the cyclosporin A‐induced stimulation of the renal NaCl cotransporter and hyperkalemic hypertension

Abstract

Aim Cyclosporin A (CsA) is a widely used immunosuppressive drug that causes hypertension and hyperkalemia. Moreover, CsA‐induced stimulation of the thiazide‐sensitive NaCl cotransporter (NCC) in the kidney has been shown to be responsible for the development of hyperkalemic hypertension. In this study, we tested whether CsA induces the activation of NCC by stimulating the basolateral Kir4.1/Kir5.1 channel in the distal convoluted tubule (DCT). Methods Electrophysiology, immunoblotting, metabolic cages, and radio‐telemetry methods were used to examine the effects of CsA on Kir4.1/Kir5.1 activity in the DCT, NCC function, and blood pressure in wild‐type (WT) and kidney‐specific Kir4.1 knockout (KS‐Kir4.1 KO) mice. Results The single‐channel patch clamp experiment demonstrated that CsA stimulated the basolateral 40 pS K+ channel in the DCT. Whole‐cell recording showed that short‐term CsA administration (2 h) not only increased DCT K+ currents but also shifted the K+ current (IK) reversal potential to the negative range (hyperpolarization). Furthermore, CsA administration increased phosphorylated NCC (pNCC) levels and inhibited renal Na+ and K+ excretions in WT mice but not in KS‐Kir4.1 KO mice, suggesting that Kir4.1 is required to mediate CsA effects on NCC function. Finally, long‐term CsA infusion (14 days) increased blood pressure, plasma K+ concentration, and total NCC or pNCC abundance in WT mice, but these effects were blunted in KS‐Kir4.1 KO mice. Conclusion We conclude that CsA stimulates basolateral K+ channel activity in the DCT and that Kir4.1 is essential for CsA‐induced NCC activation and hyperkalemic hypertension.

Deciphering the mechanism of calcineurin inhibitor‐induced hypertension

“…Cyclosporin A did not affect phosphorylated NCC levels in Kcnj10 knockout mice, in contrast to wildtype mice. In addition, cyclosporin A treatment reduced urinary sodium excretion in wildtype mice and NCC blockade by thiazide led to a greater sodium excretion in mice treated with cyclosporin A, indicative of an increased NCC activity 1 . These effects were not seen in the Kcnj10‐ deficient mice, indicating that Kir4.1 is required for the effect of calcineurin inhibitors on NCC activity.…”

“…The Kir4.1/Kir5.1 channel determines the basolateral potassium conductance in the distal convoluted tubule and plays a key role in setting the membrane potential. Interestingly, in this issue of Acta Physiologica , Gao et al show by patch‐clamp measurements that cyclosporin A stimulates Kir4.1/Kir5.1 activity in the distal convoluted tubule and makes the basolateral membrane potential more negative 1 …”

“…Therefore, decreased conductance by Kir4.1/Kir5.1 is thought to decrease NCC activity via a WNK‐SPAK signaling cascade. On the other hand, the cyclosporin‐induced activation of Kir4.1/Kir5.1 and consequent hyperpolarization of the membrane demonstrated by Gao et al is expected to decrease intracellular chloride levels, leading to stimulation of the WNK‐SPAK‐NCC pathway 1 …”

Introducing a special series: Membrane proteins, epithelial transport, and kidney physiology

“…These are just a few highlights and by no means an exhaustive overview of manuscripts published in Acta Physiologica on these topics. Furthermore, many manuscripts have been published within these fields over the latest years, including multiple recent works 9–11 …”

“…Furthermore, many manuscripts have been published within these fields over the latest years, including multiple recent works. [9][10][11] To honor this tradition, we invite you to take part in a special series on the topic of membrane proteins and epithelial transport in physiology and pathophysiology. We look forward to receiving original articles for consideration for publication in this series.…”