Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans.
Sian E PiretYiqing GuoAhmed A AttallahSylvia J HorneAmy ZollmanDaniel OwusuJustina HeneinViktoriya S SidorenkoMonica P ReveloTakashi HatoAvi Ma'ayanJohn Cijiang HeSandeep K MallipattuPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- transcription factor
- acute kidney injury
- gene expression
- genome wide identification
- chronic kidney disease
- end stage renal disease
- poor prognosis
- dna binding
- dna methylation
- genome wide
- high fat diet induced
- cardiac surgery
- induced apoptosis
- amino acid
- endothelial cells
- binding protein
- cell cycle arrest
- metabolic syndrome
- adipose tissue
- ejection fraction
- type diabetes
- long non coding rna
- oxidative stress
- wild type
- single cell
- patient reported outcomes
- high glucose
- insulin resistance
- pi k akt
- data analysis