Potential Nephroprotective Effect of uPA against Ischemia/Reperfusion-Induced Acute Kidney Injury in αMUPA Mice and HEK-293 Cells

Background/Objectives: The incidence of acute kidney injury (AKI) has been steadily increasing. Despite its high prevalence, there is no pathogenetically rational therapy for AKI. This deficiency stems from the poor understanding of the pathogenesis of AKI. Renal ischemia/hypoxia is one of the leading causes of clinical AKI. This study investigates whether alpha MUPA mice, overexpressing the urokinase plasminogen activator (uPA) gene are protected against ischemic AKI, thus unraveling a potential renal damage treatment target. Methods: We utilized an in vivo model of I/R-induced AKI in alpha MUPA mice and in vitro experiments of uPA-treated HEK-293 cells. We evaluated renal injury markers, histological changes, mRNA expression of inflammatory, apoptotic, and autophagy markers, as compared with wild-type animals. Results: the alpha MUPA mice exhibited less renal injury post-AKI, as was evident by lower SCr, BUN, and renal NGAL and KIM-1 along attenuated adverse histological alterations. Notably, the alpha MUPA mice exhibited decreased levels pro-inflammatory, fibrotic, apoptotic, and autophagy markers like TGF-beta, IL-6, STAT3, IKB, MAPK, Caspase-3, and LC3. By contrast, ACE-2, p-eNOS, and PGC1 alpha were higher in the kidneys of the alpha MUPA mice. In vitro results of the uPA-treated HEK-293 cells mirrored the in vivo findings. Conclusions: These results indicate that uPA modulates key pathways involved in AKI, offering potential therapeutic targets for mitigating renal damage.