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ClC-Kb deficiency inhibits the proliferation and mitochondrial metabolism of renal tubules

ABSTRACT: Our 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE307980 | GEO | 2026/07/09

REPOSITORIES: GEO

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Project description:Behçet syndrome (BS) is a chronic, multisystemic inflammatory condition with unanswered questions regarding its pathogenesis, classification, and rational therapeutics. A microarray-based comparative genome-wide expression analysis was performed to elucidate the molecular mechanisms of BS and identify any potential therapeutic targets. Twenty-nine BS patients (B) and 15 age and sex-matched control subjects (C) were recruited. Patients with BS were grouped as mucocutaneous (M), ocular (O), and vascular (V) according to their clinical phenotypes. GeneChip Human Genome U133 Plus 2.0 arrays were used for gene expression profiling on peripheral blood samples of the patients and the control subjects. Following the documentation of the differentially expressed gene (DEG) sets, the data were further evaluated with bioinformatics analysis/visualization and enrichment tools. Validation of the microarray data were performed using real-time qRT-PCR. When p<0.05 and fold change >2.0 were chosen, the following numbers of DEGs were obtained; B vs. C: 28, M vs. C: 20, O vs. C: 8, V vs. C: 555, M vs. O: 6, M vs. V: 324, O vs. V: 142. Venn diagram analysis indicated only two genes, CLEC12A and IFI27, in the intersection of M vs. C ∩ O vs. C ∩ V vs. C. Another noteworthy gene appeared as CLC in the DEG sets. Cluster analyses successfully clustered distinct clinical phenotypes of BS. While innate immunity-related biological processes were enriched in the M group, adaptive immunity-specific biological processes were significantly enriched in the O and V groups. Distinct clinical phenotypes of BS patients displayed distinct expression profiles. In Turkish patients with BS, expression differences regarding the genes CLEC12A, IFI27, and CLC seemed to be operative in BS pathogenesis. Based on these findings, future research should consider the immunogenetic heterogeneity of BS clinical phenotypes. Two anti-inflammatory genes, namely CLEC12A and CLC, may be valuable as therapeutic targets and may also help design an experimental model in BS.

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ClC-Kb deficiency inhibits the proliferation and mitochondrial metabolism of renal tubules

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