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 gene-targeting deletion method. Here we report that Cln7-/- mice were born viable, but died within twelve 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 to that of Cln7+/+ mice. Blood urea nitrogen and hematocrit were also significantly higher in Cln7-/- mice. The wrinkled skin was evident around one week old of Cln7-/- mice, 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 two days after birth. The significant increases of ENaC, NCC, and AQP2 mRNA levels revealed a compensatory response to the loss of electrolytes and fluid in Cln7-/- mice. Na⁺-K⁺ ATPase 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 paracellular ion transport pathway plays indispensable roles in keeping ionic balance in kidneys.