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.
Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus and is also one of the serious risk factors in cardiovascular events, end-stage renal disease, and mortality. DKD is associated with the diversified, compositional, and functional alterations of gut microbiota. The interaction between gut microbiota and host is mainly achieved through metabolites, which are small molecules produced by microbial metabolism from exogenous dietary substrates and endogenous host compounds. The gut microbiota plays a critical role in the pathogenesis of DKD by producing multitudinous metabolites. Nevertheless, detailed mechanisms of gut microbiota and its metabolites involved in the occurrence and development of DKD have not been completely elucidated. This review summarizes the specific classes of gut microbiota-derived metabolites, aims to explore the molecular mechanisms of gut microbiota in DKD pathophysiology and progression, recognizes biomarkers for the screening, diagnosis, and prognosis of DKD, as well as provides novel therapeutic strategies for DKD.
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