Activation and partial inactivation of NF-κB signaling lead to hypertension and chronic kidney disease

ABSTRACT: Activation of NF-κB-signalling is key in the pathogenesis of chronic kidney diseases (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair and hence maintain a healthy kidney. To investigate the relationship between activated and inactivated NF-κB signaling on the pathogenesis of CKD, mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine) were used. Blood pressure, serum creatinine and urinary albumin-to-creatinine-ratio markedly increased in NF-κB activated and inactivated mice compared to controls. PAS-, Masson trichrome-, and Sirius-Red-staining, as well as α-SMA immunofluorescence staining in kidneys of NF-κBC59A, and NF-κBC59S mice demonstrated kidney fibrosis in both models. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared to wild-type mice. KEGG enrichment analysis of RNA sequencing data revealed that the PPAR pathway was most markedly upregulated in both mouse models. However, there were also differences such as fatty acid degradation, peroxisome and glutathione metabolism, and downregulation of retinol metabolism in NF-κBC59A mice with decreased NF-κB signaling, whereas cell adhesion molecules, fat digestion, and absorption were upregulated in mice with activated NF-κB signaling (NF-κBC59S mice). In conclusion, using mice models with primarily activated and partially inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between kidney function as well as morphology and the activation of the NF-κB pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE244099 | GEO | 2023/09/30

REPOSITORIES: GEO