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Am J Physiol Renal Physiol 296: F847-F858, 2009. First published January 21, 2009; doi:10.1152/ajprenal.90438.2008
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PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

Kurinji Singaravelu,1,* Kishor Devalaraja-Narashimha,1,* Brynn Lastovica,2 and Babu J. Padanilam1,2

1Department of Cellular and Integrative Physiology and 2Section of Nephrology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska

Submitted 19 September 2008 ; accepted in final form 21 January 2009

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.

acute renal failure; mitochondria; caspase; AIF


Address for reprint requests and other correspondence: B. J. Padanilam, Dept. of Cellular and Integrative Physiology, Nebraska Medical Center, Omaha, NE 68198-5850 (e-mail: bpadanilam{at}unmc.edu)






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