Role of apoptosis in hypoxic/ischemic damage in the kidney.
Cell death by hypoxia/ischemia may occur by apoptosis as well as necrosis in experimental models of renal injury both in vivo and in vitro. Necrosis can occur during hypoxia/ischemia as a result of widespread cellular degradation, and during reoxygenation/reperfusion as a consequence of the development of the mitochondrial permeability transition pore (PTP). In vitro models of hypoxia/reoxygenation suggest that apoptotic cell death may occur during reoxygenation as a consequence of mitochondrial release of cytochrome c (Cyt c) during hypoxia. In hypoxic renal cells, Bax and Bak, 2 pro-apoptotic proteins of the Bcl-2 family, collaborate to permeabilize the mitochondrial outer membrane to intermembrane proteins such as Cyt c, although Bax, per se, appears to play the dominant role. Cyt c then acts to trigger the downstream apoptotic cascade. Caspase inhibitors suppress these downstream events, but not Cyt c release. However, the anti-apoptotic Bcl-2 prevents mitochondrial permeabilization and maintains viability. Inflammation is known to play a major role in exacerbating parenchymal damage during reperfusion. Recent studies suggest that the apoptosis-related mechanisms contribute to the inflammatory process. By inhibiting tubular cell apoptosis, by suppressing an apoptotic chain reaction in accumulating inflammatory cells, and by inhibiting caspase-1 processing in injured tissue, caspase inhibitors may reduce inflammation, and thereby reduce the cascading parenchymal injury that is associated with inflammation.
Saikumar
Pothana
P
Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. saikumar@uthscsa.edu
Venkatachalam
Manjeri A
MA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D007511:Ischemia / Q000473:pathology* / Q000503:physiopathology; D007674:Kidney Diseases / Q000473:pathology* / Q000503:physiopathology; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology; D012680:Sensitivity and Specificity
D019253:Proto-Oncogene Proteins c-bcl-2; D000226:Mitochondrial ADP, ATP Translocases; D020169:Caspases