Intercalated Cell Claudin‐4 knockout mice display abnormal renal sodium and potassium conservation and hypercalciuria

Abstract

Distal Renal tubular acidosis is a disease characterized by the inability to acidify the urine below a pH of 5.5, metabolic acidosis, hypokalemia and hyperchloremia. It is caused by mutations in genes encoding the v‐B1‐H+‐ATPase, the cytosolic carbonic anhydrase II or the kidney anion exchanger 1 (kAE1) in the renal collecting duct (CD). We recently discovered that kAE1 physically and functionally interacts with the tight junction protein claudin‐4 (Cldn‐4). This protein is expressed in principal (PC) and intercalated cells (IC) and forms a paracellular chloride pore and sodium barrier. With the aim to decipher the physiological role of the kAE1/Cldn‐4 interaction, we generated and characterized IC‐specific Cldn‐4 KO mouse. The knockout mice displayed a 30% reduction in Cldn‐4 abundance in isolated CD, in agreement with the reported IC/PC ratios. Although the KO animals developed normally and did not display an obvious phenotype, they presented a higher urinary calcium concentration at steady state than control animals. Feeding the mice a low NaCl diet caused the Cldn‐4 KO animals to have a more alkaline and dilute urine than control animals. Upon acid challenge, the Cldn‐4 KO mice excreted less urinary sodium and potassium compared with control animals. These results suggest that tight junction Cldn‐4 contributes to the maintenance of appropriate electrolyte and acid‐base balance.Support or Funding InformationThis work was funded by the Canadian Institutes of Health Research, the Kidney Foundation of Canada, the Women and Children's Health Research Institute (supported by the Stollery Children's Hospital Foundation), Alberta Innovates and the Canada Foundation for InnovationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.