Oridonin ameliorates hyperglycemia-induced bladder injury by promoting AMPK/PINK1/Parkin-mediated mitophagy

Diabetic bladder dysfunction (DBD), characterized by impaired detrusor contractility, decreased bladder sensation, and increased bladder compliance, remains difficult to treat due to its complex and multifactorial pathogenesis, including chronic inflammation. Oridonin (ORI), known for its strong anti-inflammatory properties, may offer therapeutic benefits for DBD. This study investigated the effects and underlying mechanisms of ORI on hyperglycemia-induced bladder injury. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to evaluate potential mechanisms. The function and molecular events of ORI in DBD were explored using both rat and cell models. GO analysis revealed that ORI primarily regulates inflammatory processes, while KEGG analysis identified the AMPK pathway as a key mechanism. Additionally, molecular docking demonstrated strong interactions between ORI and AMPK. In vivo experiments showed that ORI significantly reduced hyperglycemia-induced inflammation and mitochondrial damage, promoted AMPK phosphorylation, and increased the expression of contraction- and mitophagy-related factors. These findings were further validated in human bladder smooth muscle cells (HBSMCs) exposed to high glucose. Notably, after inhibiting AMPK-mediated mitophagy using compound C or cyclosporine A in vitro, the anti-inflammatory effects of ORI were inhibited and the expression of contraction-related proteins were down-regulated. In conclusion, ORI alleviates inflammation and reverses changes in contraction-related proteins in HBSMCs in association with changes in AMPK/PINK1/Parkin-related mitophagy markers, suggesting its potential as a novel candidate for preventing or attenuating hyperglycemia-induced bladder injury and for further investigation in the management of DBD.