Krüppel-like factor 6–mediated loss of BCAA catabolism contributes to kidney injury in mice and humans
Siân E. Piret, Yiqing Guo, Ahmed A. Attallah, Sylvia J. Horne, Amy Zollman, Daniel Owusu, Justina Henein, Viktoriya S. Sidorenko, Mónica P. Revelo, Takashi Hato, Avi Ma’ayan, John Cijiang He, Sandeep K. Mallipattu
Abstract
Significance The kidney proximal tubule is particularly susceptible to acute injury, which results in loss of fatty acid oxidation (FAO), their primary energy source. Here, we show that loss of the transcription factor KLF6 specifically in the proximal tubule in mice protects against acute injury and fibrosis, with preservation of transcripts that mediate branched-chain amino acid (BCAA) catabolism, which were down-regulated in injured control mice. BCAA may provide tricarboxylic acid cycle intermediates in the absence of FAO, and we show that loss of BCAA catabolism in vitro resulted in decreased ATP production, while pharmacological activation of BCAA catabolism increased mitochondrial oxygen consumption. Thus, preservation of BCAA catabolism may be a possible therapeutic target in acute kidney injury.