Morin attenuates vancomycin-induced nephrotoxicity via Nrf-2/HO-1, SIRT1/PGC1α and AKT/FOXO1A pathways.

BACKGROUND: Vancomycin (VCM)-induced nephrotoxicity remains a clinically important adverse effect associated with oxidative injury, inflammatory signaling, mitochondrial dysfunction, and tubular cell death. This study investigated whether Morin (MOR) could modulate these toxicological mechanisms in a rat model of VCM-induced renal injury. METHODS: Fifty adult male Sprague Dawley rats were randomly divided into five groups and treated for 7 consecutive days. On day 8, kidney tissues were collected for biochemical, histopathological, immunohistochemical, immunofluorescence, Western blot, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analyses. RESULTS: VCM administration induced marked renal injury, as evidenced by increased malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, decreased superoxide dismutase (SOD) and glutathione (GSH) levels, severe tubular degeneration, necrotic changes, and structural disruption in renal tissue. In addition, VCM significantly increased tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), receptor for advanced glycation end products (RAGE), and NLR family pyrin domain-containing 3 (NLRP3) levels, while reducing interleukin-10 (IL-10) expression. Apoptotic injury was confirmed by increased Bcl-2-associated X protein (Bax) and caspase-3 levels together with decreased B cell lymphoma 2 (Bcl-2) expression. Moreover, Kelch-like ECH-associated protein 1 (Keap-1) was upregulated, whereas nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase 1 (HO-1), sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), phosphoinositide 3-kinase (PI3K), mechanistic target of rapamycin (mTOR), and AKT serine/threonine kinase 2 (AKT2) levels were downregulated, accompanied by increased forkhead box protein O1A (FOXO1A) expression. MOR treatment, particularly at 100 mg/kg, significantly ameliorated these alterations by reducing oxidative injury, restoring endogenous defense systems, attenuating inflammatory responses, suppressing apoptosis, and markedly improving histopathological lesions. MOR also attenuated VCM-associated alterations in Keap-1/Nrf-2/HO-1-, SIRT1/PGC1α-, and PI3K/AKT2/mTOR/FOXO1A-related markers. CONCLUSIONS: Collectively, the nephroprotective effects of MOR were associated with coordinated changes in oxidative, inflammatory, apoptotic, and cell-survival markers in this experimental model.