Abstract
The p53 tumor suppressor gene plays a crucial role in mediating apoptotic cell death in renal ischemia-reperfusion injury (IRI). To further elucidate the p53-dependent pathway, we investigated the role of the p53 apoptosis effector related to PMP-22 (PERP), an apoptosis-associated p53 transcriptional target. PERP mRNA and protein are highly induced in the outer medullary proximal tubular cells (PTC) of ischemic kidneys postreperfusion at 3, 12, and 24 h in a p53-dependent manner. In PTC, overexpression of PERP augmented the rate of apoptosis following hypoxia by inducing mitochondrial permeability and subsequent release of cytochrome c, apoptosis-inducing factor (AIF), and caspase 9 activation. In addition, silencing of the PERP gene with short hairpin RNA prevented apoptosis in hypoxia-mediated injury by precluding mitochondrial dysfunction and consequent cytochrome c and AIF translocation. These data suggest that PERP is a key effector of p53-mediated apoptotic pathways and is a potential therapeutic target for renal IRI.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Inducing Factor / metabolism
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Apoptosis*
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Caspase 9 / metabolism
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Cell Hypoxia
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Cytochromes c / metabolism
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Disease Models, Animal
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Enzyme Activation
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Kidney / blood supply*
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Kidney / metabolism*
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Kidney / pathology
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LLC-PK1 Cells
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Mitochondria / metabolism
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Mitochondrial Membranes / metabolism
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Permeability
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Reperfusion Injury / metabolism*
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Reperfusion Injury / pathology
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Signal Transduction*
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Swine
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Time Factors
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Transfection
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Apoptosis Inducing Factor
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Membrane Proteins
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AIFM1 protein, mouse
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Perp protein, mouse
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RNA, Messenger
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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Cytochromes c
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Casp9 protein, mouse
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Caspase 9