The renoprotective effect of d-limonene against cisplatin-induced acute kidney injury: targeting Nrf2/HO-1 and NLRP-3 inflammasome signaling pathways

Abstract

Cisplatin is a potent chemotherapeutic agent that causes renal injury. d-limonene, a natural monoterpene, may confer renal protection. This study evaluated whether d-limonene pretreatment could mitigate cisplatin-induced nephrotoxicity. Wistar rats were divided into groups receiving vehicle, d-limonene (50 or 100 mg/kg), cisplatin (7.5 mg/kg, i.p.), or cisplatin plus d-limonene (50 or 100 mg/kg). d-limonene was administered orally once daily for 14 days, starting 7 days before and continuing 7 days after the single cisplatin injection on day 7, thus acting as both pre- and post-treatment (peri-cisplatin regimen). Cisplatin induced nephrotoxicity, shown by elevated serum urea, creatinine, uric acid, cystatin C, urine KIM-1, albumin/creatinine, and renal oxidative stress markers. It downregulated Nrf2/HO-1 and upregulated NADPH oxidase and NLRP3 inflammasome, with tubular damage histologically. d-limonene pretreatment dose-dependently improved renal dysfunction, oxidative stress, and suppressed NADPH oxidase, NLRP3, and IL-1β expression. High-dose d-limonene normalized most parameters, improved kidney histology, and renal somatic index. d-limonene mitigates cisplatin-induced nephrotoxicity with associated antioxidant and anti-inflammatory effects. The protective effect of d-limonene on cisplatin-induced nephrotoxicity through targeting oxidative stress (Nrf-2/HO-1 pathway) and inflammation (NLRP3 inflammasome)