TY - JOUR
T1 - Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans
AU - Piret, Sian E.
AU - Guo, Yiqing
AU - Attallah, Ahmed A.
AU - Horne, Sylvia J.
AU - Zollman, Amy
AU - Owusu, Daniel
AU - Henein, Justina
AU - Sidorenko, Viktoriya S.
AU - Revelo, Monica P.
AU - Hato, Takashi
AU - Ma'ayan, Avi
AU - He, John Cijiang
AU - Mallipattu, Sandeep K.
N1 - Funding Information:
This work was supported by funds from the University of Alabama at Birmingham-University of California San Diego O'Brien Center (Award P30DK079337 from the National Institute of Diabetes and Digestive and Kidney Diseases) and an American Society of Nephrology KidneyCure Joseph V. Bonventre Research Scholar Grant to S.E.P.; the Zickler Foundation, the Henry and Marsha Laufer Foundation, and National Institute for Environmental Health Sciences (1R56ES029514-01A1) to V.S.S.; NIH/National Institute for Environmental Health Sciences (DK112984, DK121846), Veterans Affairs Merit (1I01BX003698), and Dialysis Clinic, Inc. to S.K.M.; and NIH Grants (U54HL127624 and U24CA224260) to A.M. We would like to thank Dr. W. Lieberthal for supplying the samples from cisplatin-treated mice.
Funding Information:
ACKNOWLEDGMENTS. This work was supported by funds from the University of Alabama at Birmingham–University of California San Diego O’Brien Center (Award P30DK079337 from the National Institute of Diabetes and Digestive and Kidney Diseases) and an American Society of Nephrology KidneyCure Joseph V. Bonventre Research Scholar Grant to S.E.P.; the Zickler Foundation, the Henry and Marsha Laufer Foundation, and National Institute for Environmental Health Sciences (1R56ES029514-01A1) to V.S.S.; NIH/National Institute for Environmental Health Sciences (DK112984, DK121846), Veterans Affairs Merit (1I01BX003698), and Dialysis Clinic, Inc. to S.K.M.; and NIH Grants (U54HL127624 and U24CA224260) to A.M. We would like to thank Dr. W. Lieberthal for supplying the samples from cisplatin-treated mice.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/6/8
Y1 - 2021/6/8
N2 - 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.
AB - 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.
KW - Acute kidney injury
KW - Branched-chain amino acids
KW - Kidney
KW - Proximal tubule
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=85107360662&partnerID=8YFLogxK
U2 - 10.1073/pnas.2024414118
DO - 10.1073/pnas.2024414118
M3 - Article
C2 - 34074766
AN - SCOPUS:85107360662
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
M1 - e2024414118
ER -