Linagliptin increases the expression of LRP2 independent of Nrf2 in streptozotocin‐induced diabetic mice

ABSTRACT Aims/Introduction Oxidative stress is thought to play a role in the onset and progression of diabetic nephropathy (DN). Nuclear factor erythroid‐related factor 2 (Nrf2) is a master regulator of antioxidant and detoxification pathways and provides cellular protection against oxidative stress. This study aimed to examine the antioxidant effects of linagliptin, a dipeptidyl peptidase‐4 inhibitor, on DN using streptozotocin (STZ)‐induced diabetic Nrf2 knockout (Nrf2KO) mice. Materials and Methods Six‐week‐old male Nrf2KO mice and their wild‐type (WT) littermates were intraperitoneally injected with STZ (55 mg/kg) for five consecutive days to induce diabetes (DM) and/or treated with linagliptin (10 mg/kg/day) for 8 weeks. We also investigated the effects of linagliptin and high glucose concentrations on Nrf2‐mediated signaling in human renal proximal tubular epithelial cells (HRPTECs) using a NRF2‐specific siRNA. Results Despite the lack of effect on the pathological changes and higher blood glucose levels, linagliptin reduced urinary albuminuria in diabetic mice. Interestingly, linagliptin increased the expression of NADP(H): quinone oxidoreductase‐1 (NQO1) and LRP2 (megalin) in renal proximal tubular cells of WT and Nrf2KO mice, and these effects were accompanied by the activation of the AKT pathway. Linagliptin increased the expression of LRP2 under high glucose conditions through a mechanism independent of NRF2. Finally, an AKT siRNA abolished the stimulatory effects of linagliptin on LRP2 expression in HRPTECs. Conclusions These results suggested that linagliptin reduced albuminuria in individuals with DN in an NRF2‐independent manner and might exert its effects by upregulating LRP2 expression via the AKT pathway.