Krüppel-like factor 6–mediated loss of BCAA catabolism contributes to kidney injury in mice and humans

Abstract

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.

Single Cell Dissection of Epithelial-Immune Cellular Interplay in Acute Kidney Injury Microenvironment

“…The results presented here delineate the potential translation paths of PTC subtypes and PTC-S1-new may be an important node that determines fibrotic and normal repair. We also revealed injured and repair associated genes and transcription factors such as Hif ( 32 ), Irf1 ( 33 ), Klf4 ( 25 ), Hes1 ( 34 ), and Klf6 ( 26 ) ( Figures 4D, E ) involved in AKI progression, which may be important biomarkers for screening AKI progression. We also found PTC-cycling and part of PTC-new expressed proliferative markers such as Stmn1 and Pcna ( Figure 4F ).…”

“…We then analyzed the transcription characteristic between PTC-new and normal PTCs, and explored the difference between the PTC-new and normal PTCs ( Figures 3A–D ). Interestingly, most up-regulated genes or transcription factors in PTC-new were kidney injury or repair regulated genes such as Klf4 ( 25 ), Klf6 ( 26 ), Neat1 ( 27 ), Malat1 ( 28 ), and Egr1 ( 29 ) ( Figures 3A – D ). Compared to normal PTCs, the PTC-new exhibited a high level of MAPK, TNF signaling pathway and associated genes Dusp1 and Jun ( Figure 3E ), which also supported the findings that PTC-new were pro-inflammatory.…”

Urinary Metabolomic Changes Accompanying Albuminuria Remission following Gastric Bypass Surgery for Type 2 Diabetic Kidney Disease

“…Indeed, impairment of proximal tubular FAO is implicated in the pathogenesis of DKD [58]. Proximal tubularspecific knockdown of Krüppel-like factor 6 (KLF6), a transcription factor that is induced in the proximal tubule early in acute kidney injury and that suppresses BCAA catabolism, protected mice against acute renal injury and fibrosis [59]. Mice protected from acute kidney injury were demonstrated to have preserved expression of genes encoding BCAA catabolic enzymes [59].…”

“…Proximal tubularspecific knockdown of Krüppel-like factor 6 (KLF6), a transcription factor that is induced in the proximal tubule early in acute kidney injury and that suppresses BCAA catabolism, protected mice against acute renal injury and fibrosis [59]. Mice protected from acute kidney injury were demonstrated to have preserved expression of genes encoding BCAA catabolic enzymes [59]. Thus, enhanced BCAA catabolism may be implicated in the greater reduction in albuminuria observed following CSM at 2-year follow-up.…”

Modulation of gentamicin-induced acute kidney injury by myo-inositol oxygenase via the ROS/ALOX-12/12-HETE/GPR31 signaling pathway

“…In the kidney, various compartments that may be afflicted in AKI include tubular, glomerular, interstitial, and vascular compartments. The tubular compartment—especially the proximal tubules, being metabolically active—are highly amenable to ischemic or nephrotoxic injury ( 1 , 3 ). The latter may be due to the agents exogenously administered, such as aminoglycosides, like gentamicin (GEN) and cis-platinum, or such as those produced endogenously, like hemoglobin and myoglobin.…”