Polydatin Mitigates Lead-Induced Nephropathy by Modulating Oxidative Stress, Inflammation, and the AMPK/AKT/Nrf2 Pathway in Rats

Abstract

This study investigated the molecular mechanisms underlying lead (Pb)-induced nephropathy and assessed the nephroprotective potential of Polydatin (PD). Forty male Wistar rats were divided into five groups (n = 8/group): negative control (NC), normal rats treated with 200 mg/kg/day of PD (NPD200), positive control (PC) receiving Pb only (30 mg/kg/day), and two groups co-administered Pb with PD (100 or 200 mg/kg/day). Serum and urine Pb levels were determined by an atomic absorption spectrophotometer. Markers of renal tissue damage (TGF-β/iNOS/NGLA/KIM-1) and renoprotective molecules (Nrf2/AMKα/AKT1) genes and proteins were measured by quantitative RT-PCR and Immunohistochemistry, respectively. ELISA was used to quantify markers of oxidative stress (GSH/Gpx1/CAT/MDA/H₂O₂) and inflammation (TNFα/IL1β/IL6/IL-10/IFN-γ). The PC group exhibited significant renal damage, including abnormal histology, increased apoptosis, elevated serum creatinine and urea, proteinuria, and polyuria. The PC renal tissues also showed substantial upregulations of iNOS/TGF-β/KIM-1/NGAL, whilst Nrf2/AMPK/AKT declined compared to healthy rats. Moreover, levels of oxidative stress (MDA/H₂O₂) and inflammatory (TNF-α/IL1β/IL6) markers were substantially higher in the PC renal specimens, whereas the antioxidants (GSH/GPx/CAT) with IL-10 and IFN-γ decreased than the NC group. Co-administration of PD with Pb improved renal biochemical parameters, attenuated histopathological changes and apoptosis, reduced the expression of iNOS/TGF-β/KIM-1, concentrations of oxidative stress and pro-inflammatory markers, whilst enhanced antioxidants and Nrf2/AMPK/AKT/IL-10/IFN-γ levels. However, the protective effects of the PD high-dose regimen were significantly greater than the low-dose protocol. In conclusion, PD prophylactic regimens mitigated Pb-induced nephrotoxicity by targeting oxidative stress and inflammation, with the high-dose protocol demonstrating superior nephroprotective efficacy.

Keywords: Glutathione; Heavy metal-induced nephrotoxicity; Inducible nitric oxide synthase; Kidney injury molecule-1; Neutrophil gelatinase-associated lipocalin; Transforming growth factor-β.