Renal salt wasting and chronic dehydration in claudin-7-deficient mice

Tatum R, Zhang Y, Salleng K, Lu Z, Lin JJ, Lu Q, Jeansonne BG, Ding L, Chen YH. Renal salt wasting and chronic dehydration in claudin-7-deficient mice. Am J Physiol Renal Physiol 298: F24-F34, 2010. First published September 16, 2009; doi:10.1152/ajprenal.00450.2009.-Claudin-7, a member of the claudin family, is highly expressed in distal nephrons of kidneys and has been reported to be involved in the regulation of paracellular Cl- permeability in cell cultures. To investigate the role of claudin-7 in vivo, we generated claudin-7 knockout mice (Cln7(-/-)) by the gene-targeting deletion method. Here we report that Cln7(-/-) mice were born viable, but died within 12 days after birth. Cln7(-/-) mice showed severe salt wasting, chronic dehydration, and growth retardation. We found that urine Na+, Cl-, and K+ were significantly increased in Cln7(-/-) mice compared with that of Cln7(-/-) mice. Blood urea nitrogen and hematocrit were also significantly higher in Cln7(-/-) mice. The wrinkled skin was evident when Cln7(-/-) mice were similar to 1 wk old, indicating that they suffered from chronic fluid loss. Transepidermal water loss measurements showed no difference between Cln7(-/-) and Cln7(-/-) skin, suggesting that there was no transepidermal water barrier defect in Cln7(-/-) mice. Claudin-7 deletion resulted in the dramatic increase of aldosterone synthase mRNA level as early as 2 days after birth. The significant increases of epithelial Na+ channel alpha, Na+-Cl- cotransporter, and aquaporin 2 mRNA levels revealed a compensatory response to the loss of electrolytes and fluid in Cln7(-/-) mice. Na+-K+-ATPase alpha(1) expression level was also greatly increased in distal convoluted tubules and collecting ducts where claudin-7 is normally expressed. Our study demonstrates that claudin-7 is essential for NaCl homeostasis in distal nephrons, and the paracellular ion transport pathway plays indispensable roles in keeping ionic balance in kidneys.