Description
Altered cellular metabolism in kidney proximal tubule (PT) cells plays a critical role in the development and progression of acute kidney injury (AKI). The transcription factor Krppel-like factor 6 (KLF6) is rapidly and robustly induced in the PT after AKI, suggesting an early-inducible injury response gene. PT-specific Klf6 knockdown (Klf6PTKO) are protected from AKI and resulting fibrosis in mice. Combined RNA-sequencing and ChIP-sequencing demonstrated preserved expression of genes encoding branched chain amino acid (BCAA) catabolic enzymes in Klf6PTKO mice, with several of the genes also having KLF6 binding sites close to their transcription start sites. Conversely, inducible KLF6 overexpression suppressed expression of BCAA genes and exacerbated kidney injury and fibrosis in mice. Injured kidney cells could not respond to the BCAA catabolic activator BT2, and injured cells overexpressing KLF6 were less able to utilize BCAA. Thus, targeting KLF6-mediated suppression of BCAA catabolism may serve as key therapeutic target in AKI and kidney fibrosis.
Overall Design
Kidney cortex mRNA profiles were generated in Klf6fl/fl and Klf6PTKO mice treated with DMSO or AAI for 3 weeks or AAI for 3 weeks followed by 3 weeks remodeling time, using RNA-sequencing.
Curator
xm_li