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Effects of targeted Bcl-2 expression in mitochondria or endoplasmic reticulum on renal tubular cell apoptosis Bhatt K; Feng L; Pabla N; Liu K; Smith S; Dong ZAm J Physiol Renal Physiol 2008[Mar]; 294 (3): F499-507Bcl-2 family proteins are central regulators of apoptosis. As the prototypic member, Bcl-2 protects various types of cells against apoptotic insults. In mammalian cells, Bcl-2 has a dual subcellular localization, in mitochondria and endoplasmic reticulum (ER). The respective roles played by mitochondrial and ER-localized Bcl-2 in apoptotic inhibition are unclear. Using Bcl-2 constructs for targeted subcellular expression, we have now determined the contributions of mitochondrial and ER-localized Bcl-2 to the antiapoptotic effects of Bcl-2 in renal tubular cells. Wild-type Bcl-2, when expressed in renal proximal tubular cells, showed partial colocalizations with both cytochrome c and disulfide isomerase, indicating dual localizations of Bcl-2 in mitochondria and ER. In contrast, Bcl-2 constructs with mitochondria-targeting or ER-targeting sequences led to relatively restricted Bcl-2 expression in mitochondria and ER, respectively. Expression of wild-type and mitochondrial Bcl-2 showed significant inhibitory effects on tubular cell apoptosis that was induced by cisplatin or ATP depletion; however, ER-Bcl-2 was much less effective. During ATP depletion, cytochrome c was released from mitochondria into the cytosol. This release was suppressed by wild-type and mitochondrial Bcl-2, but not by ER-Bcl-2. Consistently, wild-type and mitochondrial Bcl-2, but not ER-Bcl-2, blocked Bax activation during ATP depletion, a critical event for mitochondrial outer membrane permeabilization and cytochrome c release. In contrast, ER-Bcl-2 protected against apoptosis during tunicamycin-induced ER stress. Collectively, the results suggest that the cytoprotective effects of Bcl-2 in different renal injury models are largely determined by its subcellular localizations.|Adenosine Triphosphate/metabolism[MESH]|Animals[MESH]|Anti-Bacterial Agents/adverse effects[MESH]|Antineoplastic Agents/adverse effects[MESH]|Apoptosis/*physiology[MESH]|Cell Line[MESH]|Cisplatin/adverse effects[MESH]|Cytochromes c/metabolism[MESH]|Endoplasmic Reticulum/*metabolism[MESH]|Gene Expression[MESH]|Kidney Tubules, Proximal/*metabolism[MESH]|Mitochondria/*metabolism[MESH]|Proto-Oncogene Proteins c-bcl-2/*metabolism[MESH]|Rats[MESH]|Tunicamycin/adverse effects[MESH]|bcl-2-Associated X Protein/metabolism[MESH] |
