Browsing by Author "Owusu, Daniel"

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    Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans
    (National Academy of Sciences, 2021) Piret, Sian E.; Guo, Yiqing; Attallah, Ahmed A.; Horne, Sylvia J.; Zollman, Amy; Owusu, Daniel; Henein, Justina; Sidorenko, Viktoriya S.; Revelo, Monica P.; Hato, Takashi; Ma’ayan, Avi; He, John Cijiang; Mallipattu, Sandeep K.; Medicine, School of Medicine
    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.
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    Krüppel-like factor 6–mediated loss of BCAA catabolism contributes to kidney injury in mice and humans
    (National Academy of Sciences, 2021-06-08) Piret, Sian E.; Guo, Yiqing; Attallah, Ahmed A.; Horne, Sylvia J.; Zollman, Amy; Owusu, Daniel; Henein, Justina; Sidorenko, Viktoriya S.; Revelo, Monica P.; Hato, Takashi; Ma’ayan, Avi; He, John Cijiang; Mallipattu, Sandeep K.; Medicine, School of Medicine
    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.