Oral Delivery of Nanoparticle Urolithin A Normalizes Cellular Stress and Improves Survival in Mouse Model of Cisplatin-induced AKI.

The popular anti-cancer drug cisplatin causes many adverse side-effects, the most serious of which is acute kidney injury (AKI). Emerging evidence from laboratory and clinical studies suggests that the AKI pathogenesis involves oxidative stress pathways; therefore, regulating such pathways may offer protection. Urolithin A (UA), a gut metabolite of the dietary tannin ellagic acid, possesses anti-oxidant properties, and has shown promise in mouse models of AKI. However, UA's therapeutic potential is constrained by poor bioavailability. We aimed to improve oral bioavailability of UA by formulating it into biodegradable nanoparticles that utilize a surface conjugated ligand targeting the gut-expressed transferrin receptor. Nanoparticle encapsulation of UA led to a 7-fold enhancement in oral bioavailability compared to native UA. Treatment with nanoparticle UA also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by 63% in the mouse model. Expression analyses indicated that nanoparticle UA therapy coincided with oxidative stress mitigation and downregulation of Nrf2 and P53-inducible genes. Additionally, normalization of miRNA (miR-192-5p and miR-140-5p) implicated in AKI, PARP1 levels, anti-apoptotic signaling, intracellular NAD⁺, and mitochondrial oxidative phosphorylation were observed in the treatment group. Our findings suggest that nanoparticles greatly increases the oral bioavailability of UA leading to improved survival rates in AKI mice, in part by reducing renal oxidative and apoptotic stress.