Disulfiram attenuates paraquat-induced renal injury and fibrosis accompanied by changes in Smad3 and Smad7 gene expression
TL;DR
The potential of DSF as a repurposed therapeutic candidate for mitigating paraquat-induced renal injury and fibrosis is supported and further studies evaluating protein-level changes and activation of the TGF-β/Smad signaling pathway are warranted.
Abstract
Paraquat (PQ) is a highly toxic herbicide that induces renal injury through oxidative stress and progressive fibrosis, contributing to chronic kidney disease. Drug repurposing offers a promising strategy for accelerating therapeutic development. This study evaluated the nephroprotective potential of disulfiram (DSF), a clinically approved drug with emerging antioxidant and antifibrotic properties, against PQ-induced renal injury, including its association with changes in the expression of the Smad3 and Smad7 genes. Thirty-five male Wistar rats were randomly assigned to seven groups: Control, Vehicle, DSF20, PQ (1.5 mg/kg), and PQ co-treated with DSF (5, 10, or 20 mg/kg). Renal injury was evaluated using histopathology (H&E, PAS, and Masson’s trichrome staining), α-SMA, serum biomarkers (BUN, creatinine, and uric acid), oxidative stress parameters (malondialdehyde [MDA], catalase [CAT], and glutathione peroxidase [GPx]), and Smad3 and Smad7 gene expression determined by qRT-PCR. PQ exposure caused marked renal histopathological injury, increased α-SMA, increased oxidative stress, impaired renal function, and elevated fibrosis, accompanied by increased Smad3 and decreased Smad7 gene expression. DSF co-treatment, particularly at 10 mg/kg, significantly ameliorated these changes by reducing tissue injury, decreasing α-SMA-positive area% and collagen deposition, restoring antioxidant enzyme activity, lowering lipid peroxidation, improving renal function, and altering Smad3 and Smad7 gene expression toward PQ levels. Disulfiram at an optimal dose of 10 mg/kg significantly attenuated PQ-induced renal injury and fibrosis, accompanied by reduced oxidative stress and altered Smad3 and Smad7 gene expression. These findings support the potential of DSF as a repurposed therapeutic candidate for mitigating paraquat-induced renal injury and fibrosis. Further studies evaluating protein-level changes and activation of the TGF-β/Smad signaling pathway are warranted to clarify the underlying molecular mechanisms.