Dextromethorphan induces sub-chronic nephrotoxicity via modulating renin-angiotensin system, renal xenobiotic transport and drug clearance pathway.

Dextromethorphan (DEX) is a commonly used antitussive agent and N-methyl-D-aspartate (NMDA) receptor antagonist that has been reported to cause different organ impairments. The current investigation was conducted to systematically assess the doses dependent effects of DEX on kidneys. Thirty-two Sprague Dawley rats were categorized into control group, DEX (20 mg/kg), DEX (40 mg/kg) and DEX (80 mg/kg) administered group. DEX exposure led to upregulation of Renin, angiotensin converting enzyme (ACE), and angiotensin II receptor type I (AGTR1) while downregulated the expression of angiotensin II receptor type II (AGTR2), organic anion transporter 1 (Oat1), organic anion transporter 3 (Oat3), organic cation transporter 3 (Oct2), and multidrug resistance-associated protein 2 (Mrp2) in dose-dependent manners. Moreover, DEX intoxication suppressed the activities of catalase (CAT), glutathione peroxidase (GPx), heme-oxygenase-1 (HO-1), superoxide dismutase (SOD), and glutathione reductase (GSR) while promoting the concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA). Similarly, DEX administration caused significant deterioration of renal function as indicated by significant elevations of serum urea, uric acid, blood urea nitrogen, with a marked reduction in the concentration of creatinine clearance. Furthermore, a notable upsurge was observed in the levels of kidney injury molecule-1 (KIM-1), Neutrophilic gelatinase-associated lipocalin (NGAL), N-acetyl glucosamine (NAG), Cystatin-C, Osteopontin, and Endothelin-1 after DEX exposure. Mechanistically, DEX significantly altered the apoptotic balance, elevating the levels of Bcl-2-associated protein X (Bax), cystine aspartic acid protease-3 (caspase-3), and cystine aspartic acid protease-9 (caspase-9) while reducing the levels of B-cell lymphoma-2 (Bcl-2). In parallel, DEX evoked a strong inflammatory response, which was characterized by increased concentrations of nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and cyclooxygenase-2 (COX-2). Histopathological evaluation supported these data, as it showed progressive dose-dependent renal damage from tubular degeneration to extensive glomerular collapse, interstitial edema, and inflammation. Collectively, these findings proved that sub-chronic exposure to DEX exerts a marked nephrotoxic effect via coordinated disruption of renal function, inflammatory homeostasis and apoptotic signaling. This study provides new mechanistic insights into DEX-induced renal impairments and emphasizes the importance of a strong regulatory policy.