Collecting System Specific Deletion of Kcnj10 Predisposes for Thiazide- and Low K<sup>+</sup> Diet-Induced Hypokalemia
November 07, 2019 | 05:42 PM - 05:54 PM
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Collecting System Specific Deletion of Kcnj10 Predisposes for Thiazide- and Low K+ Diet-Induced Hypokalemia
Advances in Fluid and Electrolyte Handling: Basic Physiology
November 07, 2019 | Location: 146 C, Walter E. Washington Convention Center
Abstract Time: 05:42 PM - 05:54 PM
Category: Fluid and Electrolytes
- 901 Fluid and Electrolytes: Basic
- Penton Ribas, David, University of Zurich, Zurich, Switzerland
- Vohra, Twinkle, University of Zurich, Zurich, Switzerland
- Banki, Eszter, University of Zurich, Zurich, Switzerland
- Wengi, Agnieszka, University of Zurich, Zurich, Switzerland
- Weigert, Maria, University of Regensburg, Regensburg, Germany
- Forst, Anna-Lena, University of Regensburg, Regensburg, Germany
- Bandulik, Sascha, University of Regensburg, Regensburg, Germany
- Warth, Richard, University of Regensburg, Regensburg, Germany
- Loffing, Johannes, University of Zurich, Zurich, Switzerland
David Penton Ribas, PhD
The basolateral K+ channel KCNJ10, is expressed in the renal distal convoluted tubule (DCT) and controls the activity of the thiazide-sensitive NaCl cotransporter (NCC). Loss-of-function mutations of KCNJ10 cause EAST/SeSAME syndrome with salt wasting and hypokalemia. KCNJ10 is also expressed in the principal cells of the collecting system (CS); however, its role in this segment has not been studied in detail.
To address this question, we generated the mouse model AQP2cre:Kcnj10flox/flox with a deletion of Kcnj10 specifically in the CS (CS-Kcnj10-KO).
CS-Kcnj10-KO mice responded normally to standard and high K+ diet. However, CS-Kcnj10-KO exhibited a higher kaliuresis and lower plasma K+ than control mice when treated with thiazide diuretics. Likewise, CS-Kcnj10-KO displayed an inadequately high kaliuresis and renal Na+ retention upon dietary K+ restriction. In this condition, CS-Kcnj10-KO mice became hypokalemic due to an insufficient downregulation of the epithelial Na+ channel (ENaC) and the renal outer medullary K+ channel (ROMK) in the CS. Consistently, the phenotype of CS-Kcnj10-KO was ameliorated by either pharmacological inhibition of ENaC or by genetic inactivation of ROMK in the CS.
In conclusion, KCNJ10 in the CS contributes to the renal control of K+ homeostasis by regulating ENaC and ROMK. Impaired KCNJ10 function in the CS predisposes for thiazide- and low K+ diet-induced hypokalemia and likely contributes to the pathophysiology of renal K+ loss in EAST/SeSAME syndrome.
- Government Support - Non-U.S.