Development of an anti-diabetic kidney disease drug by targeting transcriptional activity of carbohydrate responsive element binding protein (ChREBP)

More than 30% of diabetic patients will eventually develop diabetic kidney disease (DKD), characterized by the presence of elevated urinary albumin excretion and/or decreased glomerular filtration rate, resulting in end-stage renal disease. Given that present drugs can only delay the onset and progression of DKD, it is necessary to search for more effective and alternative therapeutic strategies. Our research focuses on the carbohydrate responsive element binding protein (ChREBP), a transcription factor that plays a critical role in converting excessively ingested carbohydrate into fatty acids for energy storage. While ChREBP is expressed in various metabolic tissues, including liver and adipose tissue, its physiological role in the kidney remains elusive. Our previous studies have shown that ChREBP is primarily expressed in the proximal tubular cells of the kidney and in diabetic mellitus patients, enhanced transcriptional activity of ChREBP was detected in urinary tubular cells (Suzuki et al., Endocr J, 2020). Systemic ChREBP gene depletion ameliorated a series of DKD symptoms in streptozotocin-induced mice models, prompting us to screen for specific inhibitors. In this seminar, I will present our screening results and analyze their effects in mouse models of DKD, demonstrating that ChREBP is a druggable and effective target for novel DKD therapeutic strategies.