Kidney Week

Abstract: FR-OR060

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

Session Information

• Fluids and Electrolytes: New Insights on Balance
  October 26, 2018 | Location: 8, San Diego Convention Center
  Abstract Time: 04:54 PM - 05:06 PM

Category: Fluid and Electrolytes

• 901 Fluid and Electrolytes: Basic

Authors

• Lo, Yi-Fen, Tri-Service General Hospital, Taipei City, Taiwan

Yi-Fen Lo, PhD



Dr. Chih-Jen Cheng is a physician-scientist whose major interest is ion transport in the distal renal tubule. He graduated from National Defense Medical Center in Taiwan in 2000 and earned his Ph.D. degree from UT Southwestern Medical Center at Dallas, mentored by Prof. Chou-Long Huang, in 2012. He is now the attending physician and associate professor in the Division of Nephrology, Tri-Service General Hospital, National Defense Medical Center.

• Chen, Jen-Chi, Tri-Service General Hospital, Taipei City, Taiwan

Jen-Chi Chen,

• Lin, Shih-Hua P., Tri-Service General Hospital, Taipei City, Taiwan

Shih-Hua P. Lin,

• Cheng, Chih-Jen, Tri-Service General Hospital, Taipei City, Taiwan

Chih-Jen Cheng,

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.