AKI is a multifactorial disorder characterized by the abrupt partial or complete loss of kidney functions (Fig 3). AKI leads to life-threatening complications such as pulmonary edema, hyperkalemia, and metabolic acidosis, and is also associated with high mortality rates that range between 30% and 80% world-wide.12 AKI commonly results from ischemia/reperfusion insults of the kidney, the use of nephrotoxins such as aminoglycosides and cisplatin, circulatory shock, and sepsis.13 In the United States, approximately 4% of AKI cases in critically ill patients require renal replacement

therapies and this specific form of AKI has an in-patient see more mortality rate of 50%.14 Renal replacement therapies (dialysis or organ transplantation) have significant limitations and require long-term medical care. The total number of deaths associated with

AKI in which dialysis was required rose from approximately 18,000 in the year 2000 to nearly 39,000 by 2009, more than doubling in incidence in the United States alone.15 Therefore, developing novel therapeutic treatments that are able to prevent kidney injury or trigger renal regeneration following injury has gained significant interest in the scientific community. In a normal physiological setting, cells of the mammalian kidney have a very low basal GW-572016 in vitro turnover rate. Within nephrons, cell proliferation occurs through the division of cells that reside in the tubule, which has been documented through assays such as immunoreactivity for proliferating cell nuclear antigen and Ki-67.16 and 17 A subpopulation of rare tubular epithelial cells are positive for markers of the G1 phase of the cell cycle (Fig 3, A). This data led to the hypothesis that nephrons contain resident cells that are poised to respond to damage through proliferation. 17 Indeed, proliferation rates change dramatically after epithelial injury; the vertebrate kidney possesses the remarkable

ability to repair itself by epimorphic regeneration after an ischemic insult or exposure to nephrotoxins. The marked increase in Cyclooxygenase (COX) tubular cell proliferation is considered to be the driving force behind nephron repair as opposed to cellular hypertrophy. 18 Although the mammalian tubule epithelium has the capacity to self-renew, the generation of new nephrons has not been observed and many responses to injury involve the formation of fibrotic, nonfunctional tissue. 19 The morphologic manifestations of AKI occur in multiple overlapping phases. Initially, cells at the injury site exhibit a dedifferentiated appearance associated with changes in proximal tubular cell polarity and a loss of the brush border (Fig 3, B). These cells also express genes that are associated with early nephron development, such as Paired box 2 and neural cell adhesion molecule, and mesenchymal markers like vimentin.