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Proteasome inhibition alleviates proteinuria in Lmx1b knock-in mice with dysfunctional LIM domains

ABSTRACT: LMX1B codes for a transcription factor of the LIM-homeodomain family, mutations in this gene cause the autosomal-dominant hereditary disease nail-patella syndrome. We have generated two knock-in mouse lines which carry missense mutations in the LIM domains of LMX1B and thus mimic the situation in patients. Surprisingly, both mouse lines only developed a phenotype in the recessive state. This is due to the misfolding of the respective LIM domains, in which a zinc-chelating amino acid was exchanged by an alternative amino acid, and the subsequent ubiquitin-dependent proteasomal degradation of mutant LMX1B. The proteasomal inhibitors bortezomib and MG132 stabilized the mutant proteins in vitro. A therapeutic study demonstrated that bortezomib markedly reduced podocyte damage and alleviated proteinuria in adult mice with a floxed and a knock-in Lmx1b allele. RNA sequencing of isolated podocytes from those mice revealed a number of genes which were up- or down-regulated in both knock-in mouse lines but also led to the identification to genes whose regulation specifically depended on the LIM-B domain. Our data provide proof of principle for a therapeutic strategy in patients with nail-patella syndrome suffering from missense mutations in the LIM domains of LMX1B

ORGANISM(S): Mus musculus

PROVIDER: GSE288803 | GEO | 2026/04/27

REPOSITORIES: GEO

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Project description:LMX1B is a LIM-homeodomain transcription factor essential for development. Putative LMX1B target genes have been identified through mouse gene targeting studies; however, in the absence of in vivo molecular characterization of their regulation, their identity as direct LMX1B targets remains hypothetical. We describe here the first molecular characterization of LMX1B target gene regulation. A tetracycline-inducible expression system and microarray analysis showed that a subset of NF-kappa B target genes, including IL-6 and IL-8 are upregulated in LMX1B-expressing HeLa cells. Chromatin immunoprecipitation assays revealed that LMX1B binds to the proximal promoter region of IL-6 and IL-8 in vivo, in the vicinity of the characterized kappa B site, and that LMX1B recruitment correlates with an increased NF-kappa B DNA association. Inhibition of NF-kappa B activity by short interfering RNA-mediated knock-down of p65 impairs LMX1B-dependent induction of NF-kappa B target genes, while activation of NF-kappa B activity by TNF-alpha results in a synergistic induction of these genes by LMX1B. IL-6 promoter-driven reporter assays showed that the kappa B site and an adjacent putative LMX1B binding motif are both involved in LMX1B-mediated transcription. Expression of a number of NF-kappa B target genes is affected in the kidney of Lmx1b-/- knock-out mice, thus supporting the biological relevance of the data obtained in the human cell line. Together, these data demonstrate for the first time that LMX1B directly regulates transcription of a subset of NF-kappa B target genes in cooperation with nuclear p50/p65 NF-kappa B. Human subset (GSM303547-GSM303550): Two biological replicates of non-expressing HtTA-LMX1B cells (grown in doxycycline-containing medium) and of LMX1B-expressing HtTA-LMX1B cells (grown for 4 days in doxycycline-free medium) were processed for gene expression array analyses using an Affymetrix platform. Mouse subset (GSM304379-GSM304384): Three kidney samples from newborn wild-type mice and from newborn Lmx1b-/- knock-out mice were processed for gene expression array analyses using an Agilent platform.

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Proteasome inhibition alleviates proteinuria in Lmx1b knock-in mice with dysfunctional LIM domains

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