气候变化领域集成服务门户(CCPortal): Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans

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DOI	10.1073/pnas.2024414118
	Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans
	Piret S.E.; Guo Y.; Attallah A.A.; Horne S.J.; Zollman A.; Owusu D.; Henein J.; Sidorenko V.S.; Revelo M.P.; Hato T.; Ma'ayan A.; He J.C.; Mallipattu S.K.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:23
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Acute kidney injury; Branched-chain amino acids; Kidney; Proximal tubule; Transcription factor
语种	英语
scopus关键词	adenosine triphosphate; branched chain amino acid; kruppel like factor 6; branched chain amino acid; KLF6 protein, human; Klf6 protein, mouse; kruppel like factor; kruppel like factor 6; transcription factor; acute kidney failure; adult; amino acid metabolism; animal experiment; animal model; Article; BCAA gene; chronic kidney failure; controlled study; gene; gene knockdown; gene loss; gene overexpression; gene repression; gene targeting; genetic code; human; human cell; in vitro study; kidney fibrosis; kidney function; kidney proximal tubule; KLF6 gene; mouse; nonhuman; pathogenesis; promoter region; sequence analysis; acute kidney failure; animal; disease model; gene expression regulation; genetics; inflammation; injury; kidney; metabolism; pathology; Acute Kidney Injury; Amino Acids, Branched-Chain; Animals; Disease Models, Animal; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Inflammation; Kidney; Kidney Tubules, Proximal; Kruppel-Like Factor 6; Kruppel-Like Transcription Factors; Mice; Transcription Factors
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251159
作者单位	Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, NY 11794, United States; Department of Medicine, Indiana University, Indianapolis, IN 46202, United States; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, United States; Department of Pathology, University of Utah, Salt Lake City, UT 84112, United States; Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; James J. Peters Veteran Affairs Medical Center, Bronx, NY 10468, United States; Northport Veterans Affairs Medical Center, Northport, NY 11768, United States
推荐引用方式 GB/T 7714	Piret S.E.,Guo Y.,Attallah A.A.,et al. Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans[J],2021,118(23).
APA	Piret S.E..,Guo Y..,Attallah A.A..,Horne S.J..,Zollman A..,...&Mallipattu S.K..(2021).Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans.Proceedings of the National Academy of Sciences of the United States of America,118(23).
MLA	Piret S.E.,et al."Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans".Proceedings of the National Academy of Sciences of the United States of America 118.23(2021).