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Abstract: FR-OR060

Differential Functions of Chloride Channels Clc-k1 and Clc-k2 in Mouse Kidneys

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Lo, Yi-Fen, Tri-Service General Hospital, Taipei City, Taiwan
  • Chen, Jen-Chi, Tri-Service General Hospital, Taipei City, Taiwan
  • Lin, Shih-Hua P., Tri-Service General Hospital, Taipei City, Taiwan
  • Cheng, Chih-Jen, Tri-Service General Hospital, Taipei City, Taiwan
Background

Two voltage-gated ClC chloride (Cl-) channels, ClC-Ka and ClC-Kb, conduct urinary Cl- reabsorption in renal tubules. Genetic alterations on ClC-Ka/ClC-Kb result in human diseases with abnormal blood pressure. Previous studies have shown that rodent ortholog Clc-k1 and Clc-k2 expressed in the renal medulla and cortex, respectively. The physiological roles of these two Cl- channels have not been compared.

Methods

We created Clc-k1 knockout and Clc-k2 knockout mice sharing the same genetic background using the Ksp-Cre system.

Results

Clc-k1 deficiency resulted in polyuria with a blunted response to vasopressin and relatively normal extracellular fluid. In contrast, Clc-k2 deficiency led to uncompensated renal salt wasting, hypovolemia, and impaired renal function. The sodium transporters in distal nephron were unanimously upregulated in Clc-k1 knockout mice but downregulated in Clc-k2 knockout mice. Various vasopressors, including catecholamine, endothelin, and serotonin, were stimulated in Clc-k2 knockout mice but not in Clc-k1 knockout mice. Patchy interstitial inflammation & fibrosis, hyperplasia of juxtaglomerular apparatus, and renal scarring were observed in Clc-k2 knockout mice. High salt diet rescued the renal function and ameliorated the interstitial inflammation and fibrosis in Clc-k2 knockout mice. In embryonic kidneys, Clc-k2 transcript first expressed in the nephron progenitors on E13.5 and gradually extended into the inner medulla along with NKCC2. Clc-k1 was not detected in the embryonic kidneys and found in inner medulla on P1 after birth.

Conclusion

Clc-k1 and Clc-k2 express and function differentially in the embryonic and adult kidney. The critical roles of Clc-k2 in distal salt reabsorption and embryonic kidney explain the uncompensated salt wasting in Clc-k2 knockout mice.

Funding

  • Government Support - Non-U.S.