Abstract
The pathogenesis of Bartter syndrome (BS) has long been attributed to decreased salt reabsorption in the thick ascending limb of Henle’s loop (TAL). By studying Clc-k2 (mouse ortholog of ClC-Kb)-knockout (Clc-k2-/-) mice, we recently uncovered an additional mechanism in which loss of Clc-k2 induces TAL hypoplasia in neonatal kidneys, exacerbating BS severity. Here, we further investigated this mechanism. TALs and distal convoluted tubules (DCTs) isolated from Clc-k2-/- and wild-type mice were used for transcriptome, proteomics, cell cycle, and proliferation assays. Mitochondrial morphology and function were studied using electron microscopy and mitochondrial respiration assays. Our results revealed impairments in cell proliferation, S-to-G2/M cell cycle transition, mitochondrial biogenesis, oxidative phosphorylation, glycolysis, and fatty acid oxidation in Clc-k2-/- TALs and DCTs. Increasing transport function by introducing a gain-of-function with-no-lysine kinase 4 mutation in Clc-k2-/- mice restored these metabolic and proliferative impairments and improved phenotype. Transgenic expression of peroxisome proliferator-activated receptor gamma coactivator-1α, a master regulator of mitochondrial biogenesis, in Clc-k2-/- mice also alleviated mitochondrial dysfunction and phenotype. These findings support the hypothesis that mitochondrial hypofunction, resulting from decreased transport function, contributes to cell cycle arrest and tubular hypoplasia in BS. Targeting mitochondria early in life could be a potential therapeutic approach for BS.
Authors
Chiao-Hui Hsieh, Yu-Jen Chen, Chih-Chien Sung, Emily Morrison, Chou-Long Huang, Chih-Jen Cheng
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