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

Sian E. Piret, Yiqing Guo, Ahmed A. Attallah, Sylvia J. Horne, Amy Zollman, Daniel Owusu, Justina Henein, Viktoriya S. Sidorenko, Monica P. Revelo, Takashi Hato, Avi Ma'ayan, John Cijiang He, Sandeep K. Mallipattu

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18 Scopus citations


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 (Klf6PTKD) 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 Klf6PTKD 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.

Original languageEnglish
Article numbere2024414118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number23
StatePublished - 8 Jun 2021


  • Acute kidney injury
  • Branched-chain amino acids
  • Kidney
  • Proximal tubule
  • Transcription factor


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