Protective effect of heme oxygenase induction in ischemic acute renal failure

Shimizu, Hiroko; Takahashi, Toru; Suzuki, Tsutomu; Yamasaki, Akira; Fujiwara, Tazuko; Odaka, Yasuo; Hirakawa, Masahisa; Fujita, Hideaki; Akagi, Reiko

doi:10.1097/00003246-200003000-00033

Cited by 173 publications

(131 citation statements)

References 45 publications

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“…Similar observations have been made for HO in ischemic acute renal failure (50) and for VEGF in experimental thrombotic microangiopathy (51); both genes are also target genes induced by HIF-1 activation. These observations indicate that, at least in the kidney, HIF-1 activation might result in an adaptive response to renal ischemia.…”

Section: Discussionsupporting

confidence: 81%

Functional Activation of Heat Shock Factor and Hypoxia-Inducible Factor in the Kidney

Eickelberg¹,

Seebach²,

Riordan³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Renal ischemia is the result of a complex series of events, including decreases in oxygen supply (hypoxia) and the availability of cellular energy (ATP depletion). In this study, the functional activation of two stress-responsive transcription factors, i.e., heat shock factor-1 (HSF-1) and hypoxia-inducible factor-1 (HIF-1), in the kidney was assessed. When rats were subjected to 45 min of renal ischemia, electrophoretic mobility shift assays of kidney nuclear extracts revealed rapid activation of both HIF-1 and HSF. Western blot analyses further demonstrated that this activation resulted in increased expression of the HSF and HIF-1 target genes heat shock protein-72 and heme oxygenase-1, respectively. Whether hypoxia or ATP depletion alone could produce similar activation patterns in vitro was then investigated. Renal epithelial LLC-PK 1 cells were subjected to either ATP depletion (0.1 M antimycin A and glucose deprivation) or hypoxia (1% O 2 ). After ATP depletion, HSF was rapidly activated (within 30 min), whereas HIF-1 was unaffected. In contrast, hypoxia led to the activation of HIF-1 but not HSF. Hypoxic activation of HIF-1 was observed within 30 min and persisted for 4 h, whereas no HSF activation was detected even with prolonged periods of hypoxia. HIF-1 was transcriptionally active in LLC-PK 1 cells, as demonstrated by luciferase reporter gene assays using the vascular endothelial growth factor promoter or a synthetic promoter construct containing three hypoxia-inducible elements. Interestingly, intracellular ATP levels were not affected by hypoxia but were significantly reduced by ATP depletion. These findings suggest that HIF-1 is activated specifically by decreased O 2 concentrations and not by reduced ATP levels alone. In contrast, HSF is activated primarily by metabolic stresses associated with ATP depletion and not by isolated O 2 deprivation. In vivo, the two transcription factors are simultaneously activated during renal ischemia, which might account for observed differences between in vivo and in vitro epithelial cell injury and repair. Selective modulation of either pathway might therefore be of potential interest for modification of the response of the kidney to ischemia, as well as the processes involved in recovery from ischemia.

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Section: Discussionsupporting

confidence: 81%

Functional Activation of Heat Shock Factor and Hypoxia-Inducible Factor in the Kidney

Eickelberg¹,

Seebach²,

Riordan³

et al. 2002

Journal of the American Society of Nephrology

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“…Although iCORM-3 was able to increase the levels of HO-1, it did not offer significant protection against ischemiainduced ARF in the present study. This was surprising given the number of previous studies that have demonstrated the protective effects of previous induction of HO-1 to limit renal damage after ischemia (19,20). The reason for this observation is unknown, but it is possible that because we did not detect a significant increase in HO activity by iCORM-3, the HO-1 induction failed to reach a significant threshold to afford protection against ischemia-induced ARF in the present study.…”

Section: Discussioncontrasting

confidence: 70%

“…The breakdown of heme by HO-1 leads to the production of the potent antioxidant bilirubin as well as the formation of Fe 3ϩ and CO gas. Several studies have demonstrated the protective effects of increased HO-1 activity in the kidney after ischemia (19,20); however, the precise mechanism by which increased HO-1 activity affords protection after ischemia has yet to be proved definitively. Because increased HO-1 activity is associated with an increase in bilirubin as well as CO production, it has not been possible to dissect out the contributions of each to the protective actions of HO-1 induction in the kidney after ischemia.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Carbon Monoxide–Releasing Compounds in Ischemia-Induced Acute Renal Failure

Vera

Henegar²,

Drummond³

et al. 2005

Journal of the American Society of Nephrology

129

105

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Heme oxygenase (HO) induction has been demonstrated to be beneficial in limiting the extent of cellular damage after ischemia-induced acute renal failure (ARF). Because increased HO activity is associated with the production of carbon monoxide (CO) as well as the potent antioxidant bilirubin, it is unclear which of the two is of greater importance in the protective effects of HO induction. The purpose of this study was to determine the protective role of CO alone in ischemia-induced ARF. Bilateral clamping of the renal pedicle for 40 min was associated with a ninefold increase in the levels of plasma creatinine 24 h after reperfusion as compared with normal plasma creatinine levels; however, administration of CO donor compounds tricarbonyldichlororuthenium(II) dimer, ([Ru(CO) 3 Cl 2 ] 2 , 10 mg/kg) or tricarbonylchloro(glycinato)ruthenium(II) ([Ru(CO) 3 Cl(glycinate)], (CORM-3) 1 h before the onset of ischemia significantly decreased the levels of plasma creatinine 24 h after reperfusion as compared with vehicle-treated mice. Surprising, treatment with the CO donors was associated with an increase in HO activity 24 h after ischemia. For determining whether the protective effects of the CO donors were due to CO or HO-1 induction, experiments were performed in which HO was inhibited before administration of the CO donors. Pretreatment with the HO inhibitor had no effect on the level of plasma creatinine 24 h after reperfusion after treatment with the CO donor compounds. These results suggest that CO itself may be protective and limit renal damage in ischemia induced ARF. 16: 950-958, 2005. J Am Soc Nephrol

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“…HO-1 induction occurs as an adaptive and benefi cial response to several injury processes, including oxidative injuries (Morimoto et al, 2001), rhabdomyolysis (Carstens et al, 2000), cisplatin nephrotoxicity and ARF (Shimizu et al, 2000). This may be explained by the generation of products from heme degradation, iron, carbon monoxide, biliverdin and bilirubin, which exert important antioxidant, antiinfl ammatory, and cytoprotective functions (Kirkby and Adin, 2006).…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 and hypoxia-regulated proteins are modulated by basic fibroblast growth factor in acute renal failure

et al. 2012

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Acute renal failure (ARF) can be caused by injuries that induce tissue hypoxia, which in turn can trigger adaptive or infl ammatory responses. We previously showed the participation of basic fi broblast growth factor (FGF-2) in renal repair. Based on this, the aim of this study was to analyze the effect of FGF-2 signaling pathway manipulation at hypoxia-induced protein levels, as well as in key proteins from the vasoactive systems of the kidney. We injected rat kidneys with FGF-2 recombinant protein (r-FGF) or FGF-2 receptor antisense oligonucleotide (FGFR2-ASO) after bilateral ischemia, and evaluated the presence of iNOS, EPO and HO-1, in representation of hypoxiainduced proteins, as well as COX-2, renin, kallikrein, and B2KR, in representation of the vasoactive systems of the kidney. A reduction in iNOS, HO-1, EPO, renin, kallikrein, B2KR, and in renal damage was observed in animals treated with r-FGF. The opposite effect was found with FGF-2 receptor down-regulation. In contrast, COX-2 protein levels were higher in kidneys treated with r-FGF and lower in those that received FGFR2-ASO, as compared to saline treated kidneys. These res ults suggest that the protective role of FGF-2 in the pathogenesis of ARF induced by I/R is a complex process, through which a differential regulation of metabolic pathways takes place.

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Protective effect of heme oxygenase induction in ischemic acute renal failure

Cited by 173 publications

References 45 publications

Functional Activation of Heat Shock Factor and Hypoxia-Inducible Factor in the Kidney

Functional Activation of Heat Shock Factor and Hypoxia-Inducible Factor in the Kidney

Protective Effect of Carbon Monoxide–Releasing Compounds in Ischemia-Induced Acute Renal Failure

Cyclooxygenase-2 and hypoxia-regulated proteins are modulated by basic fibroblast growth factor in acute renal failure

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