Double Knockout of Carbonic Anhydrase II (CAII) and Na+-Cl- Cotransporter (NCC) Causes Salt Wasting and Volume Depletion

Cellular Physiology and Biochemistry

关键词: Collecting duct;    Intercalated cells;    Acid base transport;    Salt absorption;   

DOI  :  10.1159/000356637

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background and Aims The thiazide-sensitive Na⁺-Cl^- cotransporter NCC and the Cl^-/HCO₃^-exchanger pendrin are expressed on apical membranes of distal cortical nephron segments and mediate salt absorption, with pendrin working in tandem with the epithelial Na⁺ channel (ENaC) and the Na⁺-dependent chloride/bicarbonate exchanger (NDCBE), whereas NCC is working by itself. A recent study showed that NCC and pendrin compensate for loss of each other under basal conditions, therefore masking the role that each plays in salt reabsorption. Carbonic anhydrase II (CAII, CA2 or CAR2) plays an important role in acid-base transport and salt reabsorption in the proximal convoluted tubule and acid-base transport in the collecting duct. Animals with CAII deletion show remodeling of intercalated cells along with the downregulation of pendrin. NCC KO mice on the other hand show significant upregulation of pendrin and ENaC. Neither model shows any significant salt wasting under baseline conditions. We hypothesized that the up-regulation of pendrin is essential for the prevention of salt wasting in NCC KO mice. Methods and Results To test this hypothesis, we generated NCC/CAII double KO (dKO) mice by crossing mice with single deletion of NCC and CAII. The NCC/CAII dKO mice displayed significant downregulation of pendrin, along with polyuria and salt wasting. As a result, the dKO mice developed volume depletion, which was associated with the inability to concentrate urine. Conclusions We conclude that the upregulation of pendrin is essential for the prevention of salt and water wasting in NCC deficient animals and its downregulation or inactivation will result in salt wasting, impaired water conservation and volume depletion in the setting of NCC inactivation or inhibition.

【 授权许可】

CC BY-NC-ND