Paola Romagnani

Localization of Injury and Repair Pathways

Abstract Acute kidney injury is an abrupt loss of glomerular filtration rate, in most cases the result of ischemic or toxic insults. The principal targets of these insults are the S3 segment of the proximal tubule and the thick ascending limb of the loop of Henle in the outer stripe of outer medulla, because these segments are characterized by high metabolic activity and they exist physiologically in relatively lower oxygen conditions. The cellular response to insults is heterogeneous with some cells undergoing death via apoptosis or necrosis, whereas others are sublethally damaged. Survived renal tubular cells that are sublethally injured activate the so-called renal stress response, an intrinsic cytoprotective response that increases the cells chance of survival, transforming potentially lethal cellular insults into sublethal forms of cell injury. The renal stress response, in addition to other adaptive mechanisms of repair, allow the cells to repair physiologic functions and restore normal architecture. For many years it was accepted that acute kidney injury was fully reversible, in particular after mild tubular injury. The renal capacity for regeneration was attributed to a diffuse proliferative response of surviving tubular cells that dedifferentiate, proliferate, migrate to denuded areas, and redifferentiate to reconstruct functional tubules. However, recent studies have questioned the ability of all tubular cells to divide and replace lost cells and demonstrated that a population of tubular progenitor cells exist in the human kidneys. These cells are scattered throughout the tubules and, despite the surrounding differentiated tubular cells, they have a more robust phenotype and a higher resistance to death. By virtue of their resistance to death, scattered progenitor cells survive the renal damages, proliferate, and replace lost tubular cells. The processes of adaptive repair and regeneration work together to restore renal function and reline the damaged nephron.