Basic ResearchCollecting system–specific deletion of Kcnj10 predisposes for thiazide- and low-potassium diet–induced hypokalemia
Graphical abstract
Section snippets
CS-Kcnj10-KO mice do not exhibit any evident clinical phenotype under standard conditions
To investigate the function of Kir4.1 in the connecting tubule and collecting duct, collecting system (CS)–specific Kcnj10-knockout mice (CS-Kcnj10-KO) were generated by breeding mice with “floxed”Kcnj10 alleles (Kcnj10flox/flox) with mice expressing the Cre recombinase under the control of the aquaporin 2 (Aqp2) promoter (Aqp2cre). CS-Kcnj10-KO mice were born in a Mendelian ratio and thrived normally. Immunofluorescence staining of consecutive kidney sections with antibodies against AQP2, Kir
Discussion
EAST/SeSAME patients suffer from loss-of-function mutations of KCNJ10 in the DCT and display severe hypokalemia and a renal tubulopathy that is reminiscent of Gitelman’s syndrome.1, 2, 3 These observations led to the current concept that the renal phenotype of patients with loss-of-function mutations in KCNJ10 is mainly due to impaired DCT function.3 According to this concept, the reduced NCC activity in patients with EAST/SeSAME syndrome results in an increased NaCl delivery to the CS. The
Animals
Mice were maintained at a 12/12-hour light/dark cycle with access to standard chow (3430 Kliba-Nafag, Kaiseraugst, Switzerland) and water ad libitum. Animal experiments were conducted according to Swiss laws and approved by the veterinary administration of the Canton of Zurich, Switzerland (license numbers 213/2015 and 135/2018). For each experimental series, animals with matching weight, sex, and age were used. CS-Kcnj10-KO mice were generated by cross-breeding Kir4.1f/f (Jackson Laboratories,
Disclosure
All the authors declared no competing interests.
Acknowledgments
The authors thank Monique Carrel, Ines Tegtmeier, Pascal Peretti, and Michèle Heidemeyer for excellent technical assistance. The authors also thank the Center of Microscopy and Image Analysis (ZMB) at the University of Zurich, and particularly Dr. Joana R. Martins, for excellent support with confocal microscopy and image analysis. The authors thank Dr. Carsten Wagner (University of Zurich, Switzerland) and Dr. Markus Bleich (University of Kiel, Germany) for fruitful discussions. Part of this
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RW and JL contributed equally to this study.