Molecular Mechanisms of Podophyllotoxin-Induced Subacute Kidney Injury: Oxidative Stress-Mediated Activation of the TRPM2-NOD-NF-κB Pathway.

BACKGROUND: Podophyllotoxin (PPT) has antitumour activity but may cause nephrotoxicity through incompletely defined mechanisms. METHODS: Male Sprague-Dawley rats received oral PPT (5 or 10mg/kg/day) for 5 days. Renal injury was evaluated by biochemical, histopathological, Raman, metabolomic, transcriptomic, targeted proteomic, and molecular analyses, followed by validation in NRK-52E cells. RESULTS: PPT at 10mg/kg reduced 24-h urine output (p < 0.05) and increased serum urea (p < 0.05), uric acid (p < 0.001), KIM-1 (p < 0.001), and lipocalin-2 (p < 0.0001). Renal GSH and CAT decreased (p < 0.001 and p < 0.01, respectively), accompanied by tubular injury, collagen deposition, and apoptosis. Trpm2 and inflammatory and matrix-remodelling genes were upregulated. PRM identified reduced LDHC, HK3, and MGST2 abundance. JNJ-28583113 attenuated PPT-induced ROS accumulation, apoptosis, Nod1/Nod2 expression, and NF-κB p65 phosphorylation. CONCLUSION: PPT induces subacute kidney injury involving oxidative stress and TRPM2-NOD-NF-κB-related inflammatory signalling.