Acute kidney injury (AKI) is one of the most powerful predictor of progressive renal failure in both native and transplanted kidneys. Although regulated death of tubular epithelial cells has long been recognized as a key feature of AKI, endothelial apoptosis is increasingly appreciated as a central factor triggering microvascular rarefaction, fibrogenesis and renal dysfunction after AKI. Our group recently demonstrated that mice genetically deficient for caspase-3 (casp3-/-), the central molecular effector of apoptosis, show accentuated renal tubular epithelial cell injury in the early stage of AKI. Yet in spite of early accentuation of tubular injury, casp3-/- are protected from renal microvascular injury and on the long term, from renal fibrogenesis. These results highlight the predominant importance of microvascular over tubular injury for setting in motion pathways that lead to renal fibrogenesis and chronic renal failure. This research project aims to build on these findings to develop a translational research strategy aimed at characterizing the molecular components within programmed death pathways that control microvascular renal damage with the ultimate goal of identifying novel predictors of progressive renal failure after AKI and novel targets of intervention.