Renal salt wasting and chronic dehydration in claudin-7-deficient mice.
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 approximately 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.
Tatum
Rodney
R
Zhang
Yuguo
Y
Salleng
Kenneth
K
Lu
Zhe
Z
Lin
Jen-Jar
JJ
Lu
Qun
Q
Jeansonne
Beverly G
BG
Ding
Lei
L
Chen
Yan-Hua
YH
D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D002712:Chlorides / Q000652:urine; D057167:Claudins; D019405:Cytochrome P-450 CYP11B2 / Q000378:metabolism; D003681:Dehydration / Q000378:metabolism* / Q000503:physiopathology; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D011188:Potassium / Q000652:urine; D012333:RNA, Messenger / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D012964:Sodium / Q000652:urine; D012965:Sodium Chloride / Q000378:metabolism*; D049992:Sodium Chloride Symporters / Q000378:metabolism
D051399:Aquaporin 2; D002712:Chlorides; D057167:Claudins; C507360:Cldn7 protein, mouse; D053503:Epithelial Sodium Channels; D008565:Membrane Proteins; D012333:RNA, Messenger; D049992:Sodium Chloride Symporters; D012965:Sodium Chloride; D012964:Sodium; D019405:Cytochrome P-450 CYP11B2; D012083:Renin; D011188:Potassium