Expression and pathophysiological significance of carbohydrate response element binding protein (Chrebp) in the renal tubules of diabetic kidney

Carbohydrate response element binding protein (ChREBP), a glucose responsive transcription factor, mainly regulates expression of genes involved in glucose metabolism and lipogenesis. Recently, ChREBP is speculated to be involved in the onset and progression of diabetic nephropathy (DN). However, there exists no report regarding the localization and function of ChREBP in the kidney. Therefore, we analyzed the localization of Chrebp mRNA expression in the wild type (WT) mice kidney using laser microdissection method, and observed its dominant expression in the proximal tubules. In diabetic mice, mRNA expression of Chrebp target genes in the proximal tubules, including Chrebpβ and thioredoxin-interacting protein (Txnip), significantly increased comparing with that of WT mice. Co-overexpression of ChREBP and its partner Mlx, in the absence of glucose, also increased TXNIP mRNA expression as well as high glucose in human proximal tubular epithelial cell line HK-2. Since TXNIP is well known to be involved in the production of reactive oxygen species (ROS), we next examined the effect of ChREBP/Mlx co-overexpression, in the absence of glucose, on ROS production in HK-2 cells. Interestingly, ChREBP/Mlx co-overexpression also induced ROS production significantly as well as high glucose. Moreover, both high glucose-induced increase of TXNIP mRNA expression and ROS production were abrogated by ChREBP small interfering RNA transfection. Taken together, high glucose-activated ChREBP in the renal proximal tubules induce the expression of TXNIP mRNA, resulting in the production of ROS which may cause renal tubular damage. It is therefore speculated that ChREBP is involved in the onset and progression of DN.