ChREBP Deficiency Suppresses Renal Inflammation and Fibrosis Via Inhibiting NLRP3 Inflammasome Activation in Diabetic Kidney Disease.

BACKGROUND AND AIM

Diabetic kidney disease (DKD) is the most-common cause of chronic renal failure and end-stage renal disease (ERSD) in diabetes mellitus (DM) patients. Renal inflammation and glomerular or interstitial fibrosis are mainly associated with the progression of DKD. Carbohydrate response element binding protein (ChREBP) is activated and transcribed in a glucose dependent manner. This study is aimed at exploring the role and underlying mechanisms of ChREBP in DKD.

METHODS

ChREBP knockout mice, obtained by CRISPR Cas9 gene editing technology, were used to study the effects of ChREBP on inflammation and fibrosis in diabetic kidney of mice. Human renal tubular epithelial (HK-2) cells were cultured in a medium containing normal or high glucose levels. Additionally, the role of ChREBP in high glucose (HG)-induced NLRP3 inflammasome activation was assessed.

RESULTS

We identified that renal inflammation, renal extracellular matrix deposition, and renal fibrosis were restored by ChREBP deficiency in diabetic mouse kidney. Consequently, ChREBP deficiency decreased the activation of nucleotide leukin-rich polypeptide 3 (NLRP3) inflammasome, which later restrained hyperglycemia-induced renal fibrosis. Importantly, NLRP3 inflammasome aggravated the above-mentioned renal fibrosis via TGF-β1 expression and the signaling pathways of Smad2/3 and the p38 MAPK. Additionally, ChREBP deficiency inhibited NLRP3 inflammasome activation both in HG-induced HK-2 cells and diabetic mouse kidney.

CONCLUSION

Our findings establish a critical role of ChREBP in engaging inflammation and renal fibrosis by regulating NLRP3 inflammasome activation in DKD.