Mechanistic insights into trimetazidine's protection against bladder ischemia-reperfusion injury via mirR-211/CHOP modulation and SIRT1/AMPK/PGC1α-mediated mitochondrial biogenesis.

Bladder ischemia, frequently associated with vascular insufficiency, contributes to lower urinary tract symptoms via oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial defect, and apoptosis. Ischemia-reperfusion (I/R) injury exacerbates these effects by generating excessive reactive oxygen species. Trimetazidine (TMZ), an anti-ischemic agent, has shown protective effects in several I/R models; however, its role in bladder injury remains insufficiently characterized. This study investigated the protective effect of TMZ against bladder I/R injury in rats, focusing on oxidative stress, inflammation, ER stress, mitochondrial biogenesis, microRNA regulation, and apoptosis. Forty rats were allocated into four groups: sham control, I/R, and two TMZ-pretreated groups (10 or 20 mg/kg/day, p.o., for 14 days) prior to I/R induction. Controls received Tween 80 vehicle. Bladder tissues were collected for biochemical, molecular, and histopathological analyses. TMZ showed protection by lowering MDA (∼43.5-60.8 %) and enhancing GSH (∼2-2.6 fold) and SOD activity (∼2-3.2 fold). ER stress was attenuated, with reduced p-PERK (∼29.4-63 %) and CHOP (∼29.1-60 %), alongside upregulation of mirR-211 (∼1.4-1.9 fold). TMZ restored mitochondrial biogenesis through increased SIRT1 (∼1.9-2.4 fold), PGC1α (∼2.1-4.3 fold), p-AMPK (∼3-6.3 fold), and ATP (∼2-2.8 fold). It also downregulated pro-apoptotic (Bax, Caspase 3) and pro-inflammatory (TNF-α, IL-1β) mediators. Histopathology revealed marked preservation of bladder architecture, particularly at 20 mg/kg. TMZ exerts strong antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective effects in bladder I/R injury via modulation of oxidative stress, ER stress, mitochondrial pathways, and the mirR-211/CHOP axis. These findings suggest that TMZ may represent a promising therapeutic candidate for ischemia-associated bladder dysfunction, providing a mechanistic basis for future translational and clinical investigation.