Affiliation:
1. Traditional Chinese Medicine Integrated Department of Nephrology The First Affiliated Hospital of Zhengzhou University Zhengzhou China
2. Institute of Nephrology Zhengzhou University Zhengzhou China
3. Henan Province Research Center for Kidney Disease Zhengzhou China
4. Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province Zhengzhou China
Abstract
AbstractAimCyclosporin 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).MethodsElectrophysiology, 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.ResultsThe 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.ConclusionWe 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.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Henan Province
Cited by
3 articles.
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