GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE307nnn/GSE307980/primary200OKTranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE307980GEOGSEfalseClC-Kb deficiency inhibits the proliferation and mitochondrial metabolism of renal tubulesOur previous study demonstrates that ClC-Kb chloride channel deficiency in Bartter syndrome (BS) type 3 not only impairs transport activity but also affects the development of the thick ascending limbs (TALs) and possibly distal convoluted tubules (DCTs). This developmental defect is important to the pathogenesis of BS, with unknown underlying mechanisms. This study investigated the cellular effects of ClC-Kb deficiency and explored potential therapeutic strategies addressing these effects. We isolated TALs and DCTs from Clc-k2(ClC-Kb mouse ortholog)-knockout (Clc-k2-/-) and wild-type mice for multi-omics analyses. The results revealed differential regulations involving cell cycle, cell proliferation, mitochondrial respiration, and metabolism. In vitro studies showed that Clc-k2-/- TALs proliferated less efficiently than wild-type cells, exhibited a G2/M cell cycle delay, had reduced mitochondrial mass and oxidative phosphorylation alongside the suppressed glycolysis and fatty acid oxidation. A gain-of-function D561A mutation in with-no-lysine kinase 4 (WNK4), known to stimulate transepithelial salt transport and mitochondrial biogenesis in TALs/DCTs, significantly restored the salt transport in Clc-k2-/- TALs/DCTs and improved the phenotype of BS. Alternatively, overexpressing Pgc1α, a master activator of mitochondrial biogenesis, also alleviated the disease severity in Clc-k2-/- mice. These findings provide insights into the molecular mechanisms of BS type 3 and suggest novel therapeutic approaches.2026/07/09GSE307980GSM9234860GSM9234859GSM9234858GSM9234855GSM9234854GSM9234857GSM9234856GSM9234853GSM923485219057307980Mus musculus