Morin hydrate mitigates renal ischemia-reperfusion injury in association with modulation of TXNIP/NLRP3 inflammasome signaling and FOXO1/PGC-1α-mediated mitochondrial regulation.

BACKGROUND: Kidney ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. This study assessed the renooprotective effects of morin hydrate (MH) and its association with inflammatory and mitochondrial regulatory pathways in an I/R rat model. METHODS: Molecular docking predicted the potential binding of MH with thioredoxin interacting protein (TXNIP)-thioredoxin (TRX) complex. Rats were assigned to four groups: sham, I/R, and I/R + MH (20 or 40 mg/kg). Renal function, oxidative stress markers, inflammatory mediators, apoptosis-related proteins, mitochondrial markers, and histopathology were assessed. RESULTS: Docking analysis suggested a potential interaction of MH with the TXNIP-TRX interface (ΔG=-8.0 kcal/mol). In vivo, MH reduced I/R-induced increase in serum creatinine and blood urea nitrogen. MH restored mitochondrial-related parameters, including NADH dehydrogenase, cytochrome c oxidase subunit 2, and ATP levels, and mitigated oxidative stress, as indicated by reduced carbonyl protein levels and restored glutathione content. MH was also associated with reduced TXNIP, NOD-like receptor protein 3 (NLRP3), and proinflammatory cytokine levels. Apoptotic markers, including phosphorylated apoptosis signal-regulating kinase 1, caspase-3, and the Bax/Bcl2 ratio, were reduced. MH was associated with downregulation of Forkhead box protein O1 (FOXO1) and dynamin-related protein-1 and, upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitofusin-1. Histological findings supported these results. CONCLUSION: MH attenuated renal I/R injury and was associated with reduced oxidative stress, inflammation, and apoptosis, along with improved mitochondrial-related parameters. These findings suggest that MH-mediated renoprotection is associated with coordinated changes in TXNIP/NLRP3 signaling and FOXO1/PGC-1α-related mitochondrial responses. Further research is necessary to elucidate the underlying mechanisms.