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Basolateral Kir4.1 activity in the distal convoluted tubule regulates K secretion by determining NaCl cotransporter activity

Wang, Wen-Hui

Current Opinion in Nephrology and Hypertension: September 2016 - Volume 25 - Issue 5 - p 429–435
doi: 10.1097/MNH.0000000000000248

Purpose of review Renal potassium (K) secretion plays a key role in maintaining K homeostasis. The classic mechanism of renal K secretion is focused on the connecting tubule and cortical collecting duct, in which K is uptaken by basolateral Na-K-ATPase and is secreted into the lumen by apical ROMK (Kir1.1) and Ca2+-activated big conductance K channel. Recently, genetic studies and animal models have indicated that inwardly rectifying K channel 4.1 (Kir4.1 or Kcnj10) in the distal convoluted tubule (DCT) may play a role in the regulation of K secretion in the aldosterone-sensitive distal nephron by targeting the NaCl cotransporter (NCC). This review summarizes recent progresses regarding the role of Kir4.1 in the regulation of NCC and K secretion.

Recent findings Kir4.1 is expressed in the basolateral membrane of the DCT, and plays a predominant role in contributing to the basolateral K conductance and in participating in the generation of negative membrane potential. Kir4.1 is also the substrate of src-family tyrosine kinase and the stimulation of src-family tyrosine kinase activates Kir4.1 activity in the DCT. The genetic deletion or functional inhibition of Kir4.1 depolarizes the membrane of the DCT, inhibits ste20-proline-alanine rich kinase, and suppresses NCC activity. Moreover, the downregulation of Kir4.1 increases epithelial Na channel expression in the collecting duct and urinary K excretion. Finally, mice with low Kir4.1 activity in the DCT are hypomagnesemia and hypokalemia.

Summary Recent progress in exploring the regulation and the function of Kir4.1 in the DCT strongly indicates that Kir4.1plays an important role in initiating the regulation of renal K secretion by targeting NCC and it may serves as a K sensor in the kidney.

Department of Pharmacology, New York Medical College, Valhalla, New York, USA

Correspondence to Wen-Hui Wang, MD, Department of Pharmacology, New York Medical College, 15 Dana Road, Valhalla, NY 10595, USA. Tel: +1 914 594 4139; fax: +1 914 347 4956; e-mail:

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