P53 Mediates the Apoptotic Response to GTP Depletion after Renal Ischemia-Reperfusion

Abstract

Abstract. 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-␣, 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-␣ was protective when given up to 14 h after the ischemic insult. The effects of pifithrin-␣ 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.

Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity

“…A previous study using a rat model of ischemia-reperfusion injury has shown that p53 protein is an important mediator of renal cell apoptosis whereby inhibition of p53 reduced ischemic injury in rats. 39 In summary, we have identified caspase-6 and -7 but not -3, -8, and -9 as transcriptional targets of p53 in renal tubular cells and the kidney cortex in response to cisplatin-induced AKI. We have characterized the p53-binding sites in the caspase-6 and -7 genes.…”

Collared Pecary (tayassu tajacu) as a new model of renal ischemic injury induced by clamping the renal artery

“…In mice , morphological changes consistent with ischemic necrosis of renal tubular cells are found after at least 30 minutes of ischemia and after over an hour of reperfusion 49,50 and in rats subjected to ischemia only renal 1 . Common findings relate to renal injury in the ischemic swine model 51 .…”

Stress-Induced p53 Runs a Direct Mitochondrial Death Program: Its Role in Physiologic and Pathophysiologic Stress Responses In Vivo

“…In this setting, the depletion of limiting intracellular pools of GTP is an important and specific physiologic inducer of apoptosis (but not of necrosis), and p53 is its critical downstream effector for mediating apoptosis. 13,14 Of note, ischemiainduced stabilization of p53 protein is to a large extent cytoplasmic rather than nuclear and more importantly, strongly colocalizes with mitochondria, as demonstrated in ischemia-reperfusion injured tubules of the outer medulla. This mitochondrial translocation correlates with apoptosis of tubular cells in vivo.…”

“…Another important pathophysiologic setting in which apoptosis is largely mediated by the mitochondrial p53 program is ischemiareperfusion injury of the kidney leading to acute renal failure, 13 a common clinical problem. Renal ischemia-reperfusion injury, modeled e.g., by transient bilateral renal artery occlusion in rat, is characterized by necrosis and apoptosis of tubular epithelial cells mainly in the outer medulla.…”

“…This mitochondrial translocation correlates with apoptosis of tubular cells in vivo. 13 Likewise, mitochondrial translocation of p53 was obtained in cultured primary proximal tubular epithelial cells subjected to chemical anoxia with antimycin A. 13 Conversely, intraperitoneally administered pifithrin-α, a highly selective and potent synthetic p53 inhibitor, 15 prevents tubular apoptosis in the outer medulla and protects renal function in mice.…”