Krappel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans

Altered cellular metabolism in kidney proximal tubule (PT) cells plays a critical role in acute kidney injury (AKI). The transcription factor Krappel-like factor 6 (KLF6) is rapidly and robustly induced early in the PT after AKI. We found that PT-specific Klf6 knockdown (Klf6(PTKD)) is protective against AKI and kidney fibrosis in mice. Com-bined RNA and chromatin immunoprecipitation sequencing analysis demonstrated that expression of genes encoding branched-chain amino acid (BCAA) catabolic enzymes was preserved in Klf6(PTKD) mice, with KLF6 occupying the promoter region of these genes. Conversely, inducible KLF6 overexpression suppressed expression of BCAA genes and exacerbated kidney injury and fibrosis in mice. In vitro, injured cells overexpressing KLF6 had similar decreases in BCAA catabolic gene expression and were less able to utilize BCAA. Furthermore, knockdown of BCKDHB, which encodes one subunit of the rate-limiting enzyme in BCAA catabolism, resulted in reduced ATP production, while treatment with BCAA catabolism enhancer BT2 increased metabolism. Analysis of kidney function, KLF6, and BCAA gene expression in human chronic kidney disease patients showed significant inverse correlations between KLF6 and both kid-ney function and BCAA expression. Thus, targeting KLF6-mediated suppression of BCAA catabolism may serve as a key therapeutic target in AKI and kidney fibrosis.

Automated summary

The altered cellular metabolism in kidney proximal tubule (PT) cells, particularly involving the transcription factor Krappel-like factor 6 (KLF6), plays a critical role in acute kidney injury (AKI) and kidney fibrosis. Targeting KLF6-mediated suppression of branched-chain amino acid (BCAA) catabolism may serve as a key therapeutic target in AKI and kidney fibrosis, as shown by protective effects in mice and inverse correlations in human chronic kidney disease patients.