Project Summary The etiology of acute kidney injury (AKI), a common disease, can be multifactorial and currently has no FDA- approved drugs for its prevention or treatment. Emerging evidence from laboratory and clinical studies suggests the pathogenesis involves reactive oxygen species (ROS) generation, activation of inflammatory and apoptotic pathways; therefore, regulating these pathways offer protection. Given the antioxidant, anti- inflammatory and antiapoptotic effects of urolithin A (UA), a gut microbial metabolite of ellagic acid, the aim of this project is to explore the therapeutic potential of UA in AKI. However, UA's therapeutic potential is constrained by poor bioavailability. The work enabled by previous findings, in which oral delivery of UA was achieved by biodegradable nanoparticles that utilize a surface conjugated ligand targeting the gut-expressed transferrin receptor. Nanoparticle encapsulation of UA led to a ~7 and ~6-fold enhancement in oral bioavailability compared to native UA in healthy rodents and dogs respectively. Treatment with nanoparticle UA also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by 63% in the mouse model. This project will further develop UA as a potential therapeutic for treating AKI, considering the fact that cisplatin is utilized only in individuals with cancer who are administered repeated low doses in the clinic. The overall goal will be accomplished by pursuing the following independent specific aims. Aim 1, will define the extent to which structural elements of the delivery system and the pathophysiology can influence UA bioavailability. Aim 2, will assess the protective benefits of the most bioavailable form of UA in dose and age dependent cisplatin-induced AKI, as well as desired and undesired effects of UA combined with cisplatin in cancer setting. Aim 3 will establish efficacy of UA against cisplatin-induced AKI in healthy dogs (non-cancerous), who will be re-homed as pets at the end of the study. At the end of the proposed studies, we will understand and fully be able to describe how effective delivery influences the pharmacology of UA, with regards to both desired and undesired effects in mice and dog models. The knowledge gained will be valuable in developing UA as not only an oral therapeutic for AKI and for other vascular and neuroinflammatory diseases in which plain UA has shown some benefit, but also as an adjuvant in combination therapies for cancer treatment, where immediate clinical testing in dogs (cancer patients) can be carried out.