P53 mediates the apoptotic response to GTP depletion after renal ischemia-reperfusion: protective role of a p53 inhibitor.
Ischemic injury to the kidney is characterized in part by nucleotide depletion and tubular cell death in the form of necrosis or apoptosis. GTP depletion was recently identified as an important inducer of apoptosis during chemical anoxia in vitro and ischemic injury in vivo. It has also been shown that GTP salvage with guanosine prevented apoptosis and protected function. This study investigates the role of p53 in mediating the apoptotic response to GTP depletion. Male Sprague-Dawley rats underwent bilateral renal artery clamp for 30 min followed by reperfusion. p53 protein levels increased significantly in the medulla over 24 h post-ischemia. The provision of guanosine inhibited the increase in p53. Pifithrin-alpha, a specific inhibitor of p53, mimicked the effects of guanosine. It had no effect on necrosis, yet it prevented apoptosis and protected renal function. Pifithrin-alpha was protective when given up to 14 h after the ischemic insult. The effects of pifithrin-alpha on p53 included inhibition of transcriptional activation of downstream p53 targets like p21 and Bax and inhibition of p53 translocation to the mitochondria. Similar results were obtained in cultured renal tubular cells. It is concluded that p53 is an important mediator of apoptosis during states of GTP depletion. Inhibitors of p53 should be considered in the treatment of ischemic renal injury.
Kelly
K J
KJ
Indiana Center for Biological Microscopy, Department of Medicine, Division of Nephrology, Indiana University, Indianapolis Indiana 46202, USA.
Plotkin
Zoya
Z
Vulgamott
Stacey L
SL
Dagher
Pierre C
PC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D052160:Benzothiazoles; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D006151:Guanosine / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000172:deficiency*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000378:metabolism; D018374:LLC-PK1 Cells; D008297:Male; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology; D014018:Tissue Distribution; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D052160:Benzothiazoles; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D006151:Guanosine; D014050:Toluene; D006160:Guanosine Triphosphate; C121565:pifithrin