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Abstract: TH-OR007

Collecting System Specific Deletion of Kcnj10 Predisposes for Thiazide- and Low K+ Diet-Induced Hypokalemia

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • 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
Background

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.

Methods

To address this question, we generated the mouse model AQP2cre:Kcnj10flox/flox with a deletion of Kcnj10 specifically in the CS (CS-Kcnj10-KO).

Results

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.

Conclusion

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.

Funding

  • Government Support - Non-U.S.