Submitted on July 27, 2008
Revised on January 21, 2009
Accepted on January 21, 2009
PERP, a p53 pro-apoptotic target, mediates apoptotic cell death in renal ischemia
Kurinji Singaravelu1, Kishor Devalaraja-Narashimha1, Brynn Lastovica, and Babu J. Padanilam1*
1 University of Nebraska Medical Center
* To whom correspondence should be addressed. E-mail: bpadanilam{at}unmc.edu.
The p53 tumor suppressor gene plays a crucial role in mediating apoptotic cell death in renal ischemia/reperfusion injury (IRI). In order to further elucidate the p53-dependent pathway, we investigated the role of PERP (p53 apoptosis effector related to PMP-22), an apoptosis-associated p53 transcriptional target. The PERP mRNA and protein are highly induced in the outermedullary proximal tubular cells (PTC) of ischemic kidneys post-reperfusion at 3, 12 and 24 hours 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, AIF, and caspase 9 activation. In addition, silencing of the PERP gene with shRNA prevented apoptosis in hypoxia mediated injury by precluding the mitochondrial dysfunction and the 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.
