PROGRAMMED CELL DEATH has been synonymous with caspasemediated apoptosis for many years, until the recent discovery of caspase-independent mechanisms of cell death. Programmed necrosis is a form of caspase-independent cell death and is currently intensively studied as a mechanism of kidney cell injury. The inner core of the kidney, known as the renal medulla, is hypertonic due to a specialized countercurrent arrangement of tubules, vascular elements, and transporters. This regional

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... is critical for body fluid osmoregulation as it provides the osmotic driving force for urinary concentration. The hypertonic environment of the kidney medulla can also promote cell death, if the physiologic cell-protective mechanisms are impaired (5). Hypertonic cell stress can induce several pathways that lead to cell death, and the distinction between hypertonicity-induced apoptosis and necrosis is becoming increasingly complex. Cells in the inner medulla are constantly exposed to high NaCl and urea concentrations, which induce osmotic stress that impairs function of intracellular proteins and disrupts the structural integrity of cell organelles. This may lead to increased reactive oxygen species formation, cytoskeletal rearrangements, decreased DNA replication, increased mitochondrial depolarization, and damaged DNA proteins (7) . To counter the hyperosmotic stress, renal medullary cells accumulate chaperones such as heat shock proteins and compatible organic osmolytes. Sudden increases in fluid tonicity or impaired protective responses can activate or induce cell death pathways. Hypertonicity-dependent mitochondrial and death receptor pathways of apoptosis have been demonstrated in different cell lines (1). Cytochrome c release is an important initial step following hypertonicity-dependent activation of the mitochondrial proapoptotic pathway in kidney cells (9). The study by Choi et al. (2) in this issue of American Journal of Physiology-Cell Physiology offers new insights into the caspase-dependent and -independent death pathways that are activated by hypertonic stress in renal epithelial cells. Using a collecting duct cell line from mouse kidney inner medulla (IMCD3), Choi et al. show that acute, lethal hypertonicity independently activates the mitochondrial, lysosomal, and death receptor pathways of apoptosis. They show that increased permeability of mitochondrial or lysosomal membranes is an early activation step, leading to cytochrome c and cathepsin B release, respectively. Furthermore, they demonstrate that neither of these early activation steps requires caspase activation. Moreover, these hypertonicity-induced cell death pathways are variably activated in different renal epithelial-derived cell lines. The findings in this study show that there is significant overlap between hypertonicity-induced activation of pathways leading to apoptosis versus programmed necrosis.