Targeting inflammation, autophagy, and apoptosis by troxerutin attenuates methotrexate-induced renal injury in rats

• Published in: International immunopharmacology 2022-02, Vol.103, p.108284-108284, Article 108284
• Main Authors: Arab, Hany H., Abd El-Aal, Sarah A., Eid, Ahmed H., Arafa, El-Shaimaa A., Mahmoud, Ayman M., Ashour, Ahmed M.
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Animals; Antioxidants; Apoptosis; Apoptosis - drug effects; Attenuation; Autophagy; Autophagy - drug effects; BAX protein; Bcl-2 protein; Cardiotoxicity; Caspase-3; Creatinine; Cyclooxygenase-2; Disease Models, Animal; Enzyme-linked immunosorbent assay; Hepatotoxicity; Histology; HMGB1 protein; Humans; Hydroxyethylrutoside - analogs & derivatives; Hydroxyethylrutoside - therapeutic use; Immune system; Immunohistochemistry; Immunomodulation; Infiltration; Inflammation; Inflammation - immunology; Injuries; Lipids; Male; Methotrexate; Methotrexate - metabolism; Neurodegeneration; NF-κB protein; Oxidative Stress; Peroxides; Rats; Rats, Wistar; Renal function; Signal Transduction; TOR protein; Troxerutin; Tumor necrosis factor-α; Vasoconstrictor Agents - therapeutic use
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.108284

[Display omitted] •Troxerutin attenuated renal immune cell infiltration and kidney function markers.•It inhibited HMGB1/RAGE/NF-κB pathway and its downstream COX-2 and TNF-α signals.•It activated the AMPK/mTOR-driven autophagy.•It lowered the apoptosis markers (caspase-3, Bax, and Bax/Bcl-2 ratio).•It curbed the oxidative stress markers and activated the Nrf2/HO-1 pathway. Troxerutin, a bioflavonoid with marked immune-modulatory and antioxidant features, has been proven to ameliorate experimental cardiotoxicity, hepatotoxicity, and neurodegeneration. However, its impact on methotrexate (MTX)-induced nephrotoxicity has not been investigated. In the current work, we aimed to investigate the potential of troxerutin to combat MTX-triggered renal injury, exploring immune cell infiltration, inflammation, autophagy, and apoptosis, with emphasis on the HMGB1/RAGE/NF-κB, AMPK/mTOR, and Nrf2/HO-1 pathways. Troxerutin (150 mg/kg/day) was administered by oral gavage and the renal tissues were examined with the aid of biochemical assays, ELISA, histology, and immunohistochemistry. Troxerutin mitigated MTX-induced renal dysfunction by significantly lowering creatinine, BUN, and KIM-1 alongside immune-cell infiltration and histopathologic aberrations. These favorable effects were mediated by inhibition of HMGB1/RAGE/NF-κB cascade via downregulating the protein expression of HMGB1, RAGE, and nuclear NF-κBp65 alongside its downstream signals, including COX-2 and TNF-α. Moreover, troxerutin activated the autophagy flux as evidenced by upregulating renal Beclin 1, lowering p62 SQSTM1 accumulation, and activation of AMPK/mTOR pathway, seen by increasing p-AMPK/total AMPK and lowering p-mTOR/total mTOR signals. In tandem, troxerutin combated renal apoptotic changes as proven with lowering caspase-3 activity, Bax expression, and Bax/Bcl-2 ratio and upregulating the proliferation signal PCNA. Additionally, the oxidative insult was attenuated by troxerutin, as evidenced by lowering NOX-1 and lipid peroxides, replenishing GSH, GPx, and SOD antioxidants, and activating Nrf2/HO-1 pathway. Troxerutin attenuated MTX-triggered renal injury via inhibition of inflammation and apoptosis alongside activation of autophagy. Thus, it may serve as an adjunct modality for the management of MTX-linked nephrotoxicity.