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

Proc Natl Acad Sci U S A. 2021 Jun 8;118(23):e2024414118. doi: 10.1073/pnas.2024414118.

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 Klf6 knockdown (Klf6 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 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 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.

Keywords: acute kidney injury; branched-chain amino acids; kidney; proximal tubule; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Amino Acids, Branched-Chain / metabolism*
  • Animals
  • Disease Models, Animal
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Inflammation
  • Kidney / injuries*
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney Tubules, Proximal / metabolism
  • Kruppel-Like Factor 6 / genetics
  • Kruppel-Like Factor 6 / metabolism*
  • Kruppel-Like Transcription Factors / genetics
  • Mice
  • Transcription Factors / metabolism

Substances

  • Amino Acids, Branched-Chain
  • KLF6 protein, human
  • Klf6 protein, mouse
  • Kruppel-Like Factor 6
  • Kruppel-Like Transcription Factors
  • Transcription Factors