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

Abstract

Altered cellular metabolism in kidney proximal tubule (PT) cells plays a critical role in acute kidney injury (AKI). The transcription factor Krüppel-like factor 6 (KLF6) is rapidly and robustly induced early in the PT after AKI. We found that PT-specific <i>Klf6</i> knockdown (<i>Klf6</i>^PTKD) is protective against AKI and kidney fibrosis in mice. Combined RNA and chromatin immunoprecipitation sequencing analysis demonstrated that expression of genes encoding branched-chain amino acid (BCAA) catabolic enzymes was preserved in <i>Klf6</i>^PTKD mice, with KLF6 occupying the promoter region of these genes. Conversely, inducible <i>KLF6</i> overexpression suppressed expression of BCAA genes and exacerbated kidney injury and fibrosis in mice. In vitro<i>,</i> injured cells overexpressing <i>KLF6</i> had similar decreases in BCAA catabolic gene expression and were less able to utilize BCAA. Furthermore, knockdown of <i>BCKDHB</i>, 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, <i>KLF6</i>, and BCAA gene expression in human chronic kidney disease patients showed significant inverse correlations between <i>KLF6</i> and both kidney function and BCAA expression. Thus, targeting KLF6-mediated suppression of BCAA catabolism may serve as a key therapeutic target in AKI and kidney fibrosis.