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Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice

ABSTRACT: The pathogenesis of Bartter syndrome (BS) has long been attributed to decreased NaCl 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 transport function induces TAL hypoplasia, exacerbating the severity of BS. 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, and 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 activity by introducing a gain-of-function with-no-lysine 4 (Wnk4) mutation in Clc-k2-/- mice restored all the abovementioned impairments and improved medulla maturation and phenotype. Transgenic overexpression of Pgc1α, a master activator 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 activity contributes to cell cycle arrest and tubular hypoplasia in BS. Targeting mitochondria early in life could be a potential therapeutic approach for BS.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Distal Convoluted Tubule, Thick Ascending Limb Of Loop Of Henle, Kidney

DISEASE(S): Bartter Disease Type 3

SUBMITTER: Chiao Hui Hsieh

LAB HEAD: Chih-Jen Cheng

PROVIDER: PXD069389 | Pride | 2026-07-09

REPOSITORIES: Pride

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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.

			Action	DRS
	2025June_ChengLab_Cdrive_search_Peaks13admin.7z	Other
	Kb01.d.zip	Other
	Kb02.d.zip	Other
	Kb03.d.zip	Other
	Kb04.d.zip	Other

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Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice

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