Upregulation of Nrf2/HO-1 signaling and farnesoid X receptor and attenuation of oxidative stress and inflammation mediate the protective effect of sitagliptin against diabetic nephropathy in rats

Diabetic nephropathy (DN) is a kidney complication associated with diabetes that can lead to renal failure. The dipeptidyl peptidase IV inhibitor sitagliptin (SITA) has shown potential therapeutic benefits for DN. This study investigated the effect of SITA on DN, focusing on its modulation of the farnesoid X receptor (FXR) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling and its suppressive efficacy on inflammation and oxidative stress. Thirty-two male rats were divided into four groups: control, SITA-treated, diabetic, and SITA-treated diabetic rats. SITA was administered orally for 8 weeks to diabetic rats induced with streptozotocin, after which samples were collected for analysis. The results indicate that SITA effectively reduced hyperglycemia, weight loss, and kidney injury and fibrosis. SITA also decreased oxidative stress, inflammatory markers, and apoptosis, as demonstrated by reductions in kidney malondialdehyde (MDA), myeloperoxidase, nitric oxide (NO), nuclear factor-kappaB (NF-κB), interleukin (IL)-1β, inducible NO synthase (iNOS), tumor necrosis factor (TNF)-α, Bcl-2-associated X protein (Bax), and caspase-3. These protective effects were associated with Kelch-like ECH-associated protein (Keap)-1 inhibition, increased levels of Nrf2 and FXR, and enhanced antioxidant activity as well as Bcl-2 upregulation. In silico analysis showed the binding of SITA with FXR, NF-κB p65, iNOS, Keap-1, caspase-3, and HO-1. In conclusion, SITA mitigates DN by reducing hyperglycemia, inflammation, and oxidative stress, while enhancing antioxidant defenses, FXR and Nrf2/HO-1 signaling. [Abstract copyright: Copyright © 2025 Elsevier B.V. All rights reserved.]