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Activation of Kir4.1/Kir5.1 contributes to the cyclosporin A-induced stimulation of the renal NaCl cotransporter and hyperkalemic hypertension.
Gao, Zhong-Xiuzi; Zhou, Rui; Li, Ming-Yan; Li, Shu-Ting; Mao, Zi-Hui; Shu, Ting-Ting; Liu, Dong-Wei; Liu, Zhang-Suo; Wu, Peng.
Afiliação
  • Gao ZX; Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • Zhou R; Institute of Nephrology, Zhengzhou University, Zhengzhou, China.
  • Li MY; Henan Province Research Center for Kidney Disease, Zhengzhou, China.
  • Li ST; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
  • Mao ZH; Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • Shu TT; Institute of Nephrology, Zhengzhou University, Zhengzhou, China.
  • Liu DW; Henan Province Research Center for Kidney Disease, Zhengzhou, China.
  • Liu ZS; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
  • Wu P; Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Acta Physiol (Oxf) ; 238(2): e13948, 2023 06.
Article em En | MEDLINE | ID: mdl-36764674
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hiperpotassemia / Hipertensão Limite: Animals Idioma: En Revista: Acta Physiol (Oxf) Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hiperpotassemia / Hipertensão Limite: Animals Idioma: En Revista: Acta Physiol (Oxf) Ano de publicação: 2023 Tipo de documento: Article