PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

Singaravelu, Kurinji; Devalaraja-Narashimha, Kishor; Lastovica, Brynn; Padanilam, Babu J.

doi:10.1152/ajprenal.90438.2008

Cited by 24 publications

(27 citation statements)

References 48 publications

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“…Both oxidative stress and ischemia have been reported to increase the number of apoptotic cells within the kidney (20,31,39); therefore, we investigated the extent of renal cell apoptosis using the TUNEL assay on formalin-fixed kidneys. Levels of apoptosis tended to be elevated in both the servo-controlled and uncontrolled kidneys compared with kidneys from saline-infused sham rats, but did not reach levels of statistical significance.…”

Section: Discussionmentioning

confidence: 99%

Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

Polichnowski

Lü

Cowley

2011

American Journal of Physiology-Renal Physiology

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Polichnowski AJ, Lu L, Cowley A Jr. Renal injury in angiotensin IIϩL-NAME-induced hypertensive rats is independent of elevated blood pressure. Am J Physiol Renal Physiol 300: F1008-F1016, 2011. First published January 26, 2011 doi:10.1152/ajprenal.00354.2010.-The balance between angiotensin II (ANG II) and nitric oxide plays an important role in renal function and is thought to contribute to the progression of renal injury in experimental hypertension. In the present study, we investigated the extent of blood pressure (BP)-dependent and BP-independent pathways of renal injury following 2 wk of hypertension produced by intravenous infusion of ANG II (5 ng·kg Ϫ1 ·min Ϫ1)ϩN -nitro-L-arginine methyl ester (L-NAME; 1.4 g·kg Ϫ1 · min Ϫ1 ) in male Sprague-Dawley rats. An aortic balloon occluder was positioned between the renal arteries to maintain (24 h/day) BP to the left kidney (servo-controlled) at baseline levels, whereas the right kidney (uncontrolled) was chronically exposed to elevated BP. Over the 14-day experimental protocol, the average BP to uncontrolled kidneys (152.7 Ϯ 1.8 mmHg) was significantly elevated compared with servo-controlled (113.0 Ϯ 0.2 mmHg) kidneys and kidneys from sham rats (108.3 Ϯ 0.1 mmHg). ANG IIϩL-NAME infusion led to renal injury that was focal in nature and mainly confined to the outer medulla. Despite the differences in BP between servo-controlled and uncontrolled kidneys, there was a similar ϳ3.5-fold increase in renal outer medullary tubular injury, ϳ2-fold increase in outer medullary interstitial fibrosis, ϳ2-fold increase in outer medullary macrophage infiltration, and a significant increase in renal oxidative stress, all of which are indicative of BP-independent mediated pathways. The results of this study have important implications regarding the pathogenesis of renal injury in various experimental models of hypertension and provide novel insights regarding the variable association observed between hypertension and renal injury in some human populations. hypertension; angiotensin II; nitric oxide; inflammation; oxidative stress THE PROGRESSION OF RENAL DAMAGE varies widely among hypertensive populations (10,17,36,43) as well as in experimental models of hypertension (2, 29). While elevated blood pressure (BP), per se, clearly plays a dominant role in the progression of renal injury in many forms of hypertension (2,25,29), it is also understood that renal injury continues to worsen in some individuals despite optimal BP control (10,17,45). Several such BP-independent mechanisms have been proposed and are thought to directly contribute to renal injury and/or alter the susceptibility to BP-induced renal injury and broadly include genetic-, dietary-, and neurohumoral-related mechanisms. We have recently reported that elevated circulating levels of ANG II increase the susceptibility to both BP-dependent and BPindependent pathways of tubulointerstitial injury and fibrosis compared with equivalent pressor doses of norepinephrine (NE) (29). A better understanding of the mechanisms tha...

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Section: Discussionmentioning

confidence: 99%

Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

Polichnowski

Lü

Cowley

2011

American Journal of Physiology-Renal Physiology

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“…Tissue sections were then mounted for evaluation under Leica fluorescent microscope with appropriate filters Cell culture and hypoxic injury. Cell culture and hypoxic injury were performed as previously described (41). Briefly, hypoxic culture conditions (oxygen level Ͻ2%) were achieved with a pouch system providing a CO2-enriched anaerobic environment (BBL GasPak Pouch System, Becton Dickinson) as previously reported (50).…”

Section: Methodsmentioning

confidence: 99%

“…Quantification of cells undergoing apoptotic cell death by flow cytometry analysis was performed as we previously described using the Telford method (41).…”

Section: Methodsmentioning

confidence: 99%

p53 target Siva regulates apoptosis in ischemic kidneys

Singaravelu

Padanilam

2011

American Journal of Physiology-Renal Physiology

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The role of p53 in inducing apoptosis following acute kidney injury is well-established; however, the molecular mechanisms remain largely unknown. We report here that the p53 proapoptotic target Siva and its receptor CD27, a member of the tumor necrosis factor receptor family, are upregulated following renal ischemia-reperfusion injury (IRI). Inhibition of Siva using antisense oligonucleotides conferred functional and morphological protection, and it prevented apoptosis postrenal IRI in mice. Renal IRI in CD27-deficient mice displayed functional protection and partial inhibition of apoptosis, suggesting an incomplete role for CD27 in Siva-mediated apoptosis. To further elucidate mechanisms by which Siva elicits apoptosis, in vitro studies were performed. In Siva-transfected LLC-PK(1)cells, Siva is persistently expressed in the nucleus at 3 h onwards and its translocation to mitochondria and the plasma membrane occurred at 6 h. Moreover, Siva overexpression induced mitochondrial permeability, cytochrome c release, caspase-8 and -9 activation, translocation of apoptosis-inducing factor (AIF) to the nucleus, and apoptosis. Inhibition of Siva in ischemic kidneys prevented mitochondrial release of cytochrome c and AIF. These data indicate that Siva function is pivotal in regulating apoptosis in the pathology of renal IRI. Targeting Siva may offer a potential therapeutic strategy for renal IRI.

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“…p53 has also been shown to play a crucial role in mediating apoptotic cell death in renal ischemia-reperfusion injury (Wada et al 2005;Wada et al 2008), a common cause of acute kidney injury that is characterized by widespread tubular and microvascular apoptosis (Dagher 2004;Hochegger et al 2007;Sutton et al 2008;Singaravelu et al 2009;Molitoris et al 2009). It was suggested that an apoptosisassociated p53 transcriptional target PERP can play a key role in p53-mediated apoptotic pathways (Singaravelu et al 2009).…”

Section: P53 and Pathologies Associated With Acute Ischemiamentioning

confidence: 99%

“…It was suggested that an apoptosisassociated p53 transcriptional target PERP can play a key role in p53-mediated apoptotic pathways (Singaravelu et al 2009). …”

Section: P53 and Pathologies Associated With Acute Ischemiamentioning

confidence: 99%

Pathologies Associated with the p53 Response

Gudkov¹,

Komarova²

2010

Cold Spring Harbor Perspectives in Biology

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PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

Abstract: Singaravelu K, Devalaraja-Narashimha K, Lastovica B, Padanilam BJ. PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia.

Cited by 24 publications

References 48 publications

Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

p53 target Siva regulates apoptosis in ischemic kidneys

Pathologies Associated with the p53 Response

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