LBODP050 Examination Of The Effectiveness Of Diabetic Nephropathy Treatment Targeting Chrebp Activity

Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and is characterized by elevated urinary albumin to creatinine ratio (UACR) and serum creatinine, and decreased glomerular filtration rate. Anti hypertensive agents are used for DN treatment, however, the effects of these drugs are insufficient, and the establishment of more effective treatment methods is desired. Carbohydrate responsive element binding protein (ChREBP) is one of the factors reported to be involved in the onset and progression of DN (1). Furthermore, whole body ablation of ChREBP suggested that the progression of DN was suppressed in the rodent model (2). On the other hand, the effectiveness of pharmaceutical ChREBP suppression is unclear, thus, we performed administration experiment to DN model mice using ChREBP activity inhibitor and examined the effects of pharmaceutical ChREBP activity suppression on renal function of diabetic mice. First, we established high-throughput screening system capable of detecting ChREBP activity and performed screening of Tohoku university compound library. The result compound, D-532, was ChREBP activity specific inhibitor without cell toxicity. D-532 directly binds to DNA-binding domain of ChREBP, and inhibits the transcriptional activity. We next performed administration experiment using type I DN model mice. D-532 treatment group showed an improvement tendency of the low body weight compared with that of vehicle treatment group, while it had no effect on blood glucose level. About renal functions, both of UACR and serum creatinine were significantly lower in D-532 treatment group. Importantly, renal tissues such as glomeruli and renal tubules were preserved in D-532 treatment group compared with in vehicle treatment group. In vivo as well, D-532 suppressed ChREBP target genes mRNA expression, and RNA-seq analysis with mice renal cortex RNA at the end of D-532 administration experiment indicated that D-532 suppressed excessive oxidative stress through the ChREBP activation under diabetes. These results indicate that ChREBP suppression is effective on DN rodent model, and ChREBP activity inhibitor D-532 may have potential as a new treatment for DN in the future. Reference: (1) Suzuki et al., Endocr J. 2019 Mar 28;67(3): 335-345. (2) Zhang et al., Eur Rev Med Pharmacol Sci. 2017 Jan;21(1): 42-47. Presentation: No date and time listed