Abstract
Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus for which there is still no effective treatment. We previously showed that upregulation of thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of thioredoxin (TRX), accelerates the progression of DKD. In this study, we hypothesized whether verapamil, a calcium channel blocker and an established TXNIP inhibitor, might exert a renal-protective effect on DKD by regulating TXNIP expression. Herein, a systemic pharmacological network study was performed and multiple molecules and pathways targeted by verapamil on DKD were characterized. Furthermore, diabetic mice were induced by streptozotocin (STZ), and verapamil (100 mg/kg/day) or saline was intraperitoneally injected into the mice. After 16 weeks, mice were analyzed for blood glucose, blood pressure, and functional parameters followed by sacrifice and evaluation of renal tubular injury, alterations in TXNIP, apoptosis and fibrosis markers. Additionally, the effects of treatment with verapamil (50 μM, 100 μM, 150 μM) under high glucose conditions on the expression of TXNIP and signaling pathway components in proximal tubular epithelial cells (PTEC, HK-2 cells) were explored. According to these findings, we conclude that verapamil might serve as a potential agent for the prevention and treatment of DKD.