Penton, David and Vohra, Twinkle and Banki, Eszter and Wengi, Agnieszka and Weigert, Maria and Forst, Anna-Lena and Bandulik, Sascha and Warth, Richard and Loffing, Johannes (2020) Collecting system-specific deletion of Kcnj10 predisposes for thiazide- and low-potassium diet-induced hypokalemia. KIDNEY INTERNATIONAL, 97 (6). pp. 1208-1218. ISSN 0085-2538, 1523-1755
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The basolateral potassium channel KCNJ10 (Kir4.1), is expressed in the renal distal convoluted tubule and controls the activity of the thiazide-sensitive sodium chloride cotransporter. Loss-of-function mutations of KCNJ10 cause EAST/SeSAME syndrome with salt wasting and severe hypokalemia. KCNJ10 is also expressed in the principal cells of the collecting system. However, its pathophysiological role in this segment has not been studied in detail. To address this, we generated the mouse model AQP2cre:Kcnj10flox/flox with a deletion of Kcnj10 specifically in the collecting system (collecting systemKcnj10-knockout). Collecting system-Kcnj10-knockout mice responded normally to standard and high potassium diet. However, this knockout exhibited a higher kaliuresis and lower plasma potassium than control mice when treated with thiazide diuretics. Likewise, collecting systemKcnj10-knockout displayed an inadequately high kaliuresis and renal sodium retention upon dietary potassium restriction. In this condition, these knockout mice became hypokalemic due to insufficient downregulation of the epithelial sodium channel (ENaC) and the renal outer medullary potassium channel (ROMK) in the collecting system. Consistently, the phenotype of collecting systemKcnj10-knockout was fully abrogated by ENaC inhibition with amiloride and ameliorated by genetic inactivation of ROMK in the collecting system. Thus, KCNJ10 in the collecting system contributes to the renal control of potassium homeostasis by regulating ENaC and ROMK. Hence, impaired KCNJ10 function in the collecting system predisposes for thiazide and low potassium diet-induced hypokalemia and likely contributes to the pathophysiology of renal potassium loss in EAST/SeSAME syndrome.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DISTAL CONVOLUTED TUBULE; SODIUM-CHLORIDE COTRANSPORTER; II BARTTERS-SYNDROME; SENSORINEURAL DEAFNESS; NA CHANNELS; MOUSE MODEL; K+; EXPRESSION; NCC; CL; collecting duct; connecting tubule; dietary potassium; diuretics; hypokalemia; potassium homeostasis |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Richard Warth |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Mar 2021 12:01 |
| Last Modified: | 22 Mar 2021 12:01 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44474 |
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