Dipyridamole Confers Renoprotection Against Rhabdomyolysis-Induced Acute Kidney Injury via Modulation of Oxidative Stress, the PKC/ET-1/PI3K/AKT Signaling Axis, and Apoptosis

Background: Rhabdomyolysis (RM)-induced acute kidney injury (RIAKI) is a common clinical complication with an increasing incidence. Despite optimal care, the mortality rate is almost 15% due to limited pharmacological interventions. Dipyridamole (DPM), a non-selective phosphodiesterase inhibitor, possesses antioxidant, anti-inflammatory, and antiproliferative properties. This study aimed to investigate the protective effect of DPM against glycerol (GLY)-induced RIAKI, focusing on key AKI-related signaling pathways, including the protein kinase C (PKC)/endothelin-1 (ET-1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mitogen-activated protein kinase (MAPK) cascade, and apoptotic and proliferative responses. Methods: Rats were randomly assigned to five groups: control, DPM control, GLY, DPM (10 mg/kg) + GLY, and DPM (20 mg/kg) + GLY. DPM was administered intraperitoneally for 8 days. Notably, the DPM CTRL group received DPM at 20 mg/kg, with no DPM-alone (10 mg/kg) group included. Twenty-four hours later, blood and kidneys were collected. Kidney function, oxidative stress, histopathological changes, and PKC/ET-1/PI3K/AKT/MAPK signaling were evaluated. Additionally, apoptotic markers, Bax and P53, and proliferation-related markers, Ki67 and VEGFA, were assessed immunohistochemically. Results: DPM significantly improved kidney function and preserved renal architecture. DPM attenuated oxidative stress, suppressed PKC and ET-1, and modulated the PI3K/AKT/MAPK signaling. Moreover, DPM downregulated Bax and P53 and reduced Ki67 and VEGFA, reflecting attenuation of injury-associated signaling rather than impaired renal repair. Conclusions: DPM exerted renoprotective effects against GLY-induced RM-associated AKI through multiple complementary mechanisms.