The role of heme oxygenase 1 in rapamycin-induced renal dysfunction after ischemia and reperfusion injury

Gonçalves, Giselle Martins; Cenedeze, Marcos Antônio; Feitoza, Carla Q.; Wang, P.M.H.; Bertocchi, Ana Paula Fernandes; Damião, Marcio José; Sanders-Pinheiro, Hélady; Teixeira, Vicente P. A.; Reis, Marlene Antônia dos; Pacheco-Silva, Álvaro; Câmara, Niels Olsen Saraiva

doi:10.1038/sj.ki.5001893

Cited by 65 publications

(55 citation statements)

References 45 publications

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“…In addition, the enhanced HO-1 expression was specific to rapamycin, as no induction was observed in the presence of cyclosporine, and it was responsible for rapamycin antiproliferative capacity. Rapamycin delayed renal tubular regeneration and caused increased levels of renal dysfunction in the ischemic renal injury mouse model (57). HO-1 was upregulated after ischemic renal injury, and its expression was enhanced by rapamycin.…”

Section: Effect Of Ho-1 Interactions With Drug and Growth Factors On mentioning

confidence: 97%

Heme oxygenase: the key to renal function regulation

Abraham

Cao

Sacerdoti

et al. 2009

American Journal of Physiology-Renal Physiology

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Heme oxygenase (HO) plays a critical role in attenuating the production of reactive oxygen species through its ability to degrade heme in an enzymatic process that leads to the production of equimolar amounts of carbon monoxide and biliverdin/bilirubin and the release of free iron. The present review examines the beneficial role of HO-1 (inducible form of HO) that is achieved by increased expression of this enzyme in renal tissue. The influence of the HO system on renal physiology, obesity, vascular dysfunction, and blood pressure regulation is reviewed, and the clinical potential of increased levels of HO-1 protein, HO activity, and HO-derived end products of heme degradation is discussed relative to renal disease. The use of pharmacological and genetic approaches to investigate the role of the HO system in the kidney is key to the development of therapeutic approaches to prevent the adverse effects that accrue due to an impairment in renal function.

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Section: Effect Of Ho-1 Interactions With Drug and Growth Factors On mentioning

confidence: 97%

Heme oxygenase: the key to renal function regulation

Abraham

Cao

Sacerdoti

et al. 2009

American Journal of Physiology-Renal Physiology

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“…HO-1 protects against IR injury in many organs. For example, inhibition of HO-1 with SnPP increases renal dysfunction after IR (13). Induction of HO-1 expression by tetramethylpyrazine attenuates rat myocardial infarction after IR (6).…”

Section: Protection Of Phi Against the Mpt And Ir Injury Is Mediatedmentioning

confidence: 99%

Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion

Zhong

Ramshesh²,

Rehman³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Zhong Z, Ramshesh VK, Rehman H, Currin RT, Sridharan V, Theruvath TP, Kim I, Wright GL, Lemasters JJ. Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 295: G823-G832, 2008. First published September 4, 2008 doi:10.1152/ajpgi.90287.2008.-The mitochondrial permeability transition (MPT) plays an important role in hepatocyte death caused by ischemia-reperfusion (IR). This study investigated whether activation of the cellular oxygen-sensing signal cascade by prolyl hydroxylase inhibitors (PHI) protects against the MPT after hepatic IR. Ethyl 3,4-dihyroxybenzoate (EDHB, 100 mg/kg ip), a PHI, increased mouse hepatic hypoxia-inducible factor-1␣ and heme oxygenase-1 (HO-1). EDHB-treated and untreated mice were subjected to 1 h of warm ischemia to ϳ70% of the liver followed by reperfusion. Mitochondrial polarization, cell death, and the MPT were assessed by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. EDHB largely blunted alanine aminotransferase (ALT) release and necrosis after reperfusion. In vehicle-treated mice at 2 h after reperfusion, viable cells with depolarized mitochondria were 72%, and dead cells were 2%, indicating that depolarization preceded necrosis. Mitochondrial voids excluding calcein disappeared, indicating MPT onset in vivo. NIM811, a specific inhibitor of the MPT, blocked mitochondrial depolarization after IR, further confirming that mitochondrial depolarization was due to MPT onset. EDHB decreased mitochondrial depolarization to 16% and prevented the MPT. Tin protoporphyrin (10 mol/kg sc), an HO-1 inhibitor, partially abrogated protection by EDHB against ALT release, necrosis, and mitochondrial depolarization. In conclusion, IR causes the MPT and mitochondrial dysfunction, leading to hepatocellular death. PHI prevents MPT onset and liver damage through an effect mediated partially by HO-1. ethyl 3,4-dihyroxybenzoate; heme oxygenase; hepatic ischemia-reperfusion; mitochondrial permeability transition; prolyl hydroxylase inhibitor ISCHEMIA-REPERFUSION (IR) injury to the liver occurs in trauma, hemorrhagic and cardiac shock, vascular diseases, and hepatic surgery, including tumor resection and liver transplantation. A variety of pathophysiological processes likely contribute to development of IR injury. Reactive oxygen species (ROS) play a critical role in the injury caused by IR (18,36,57). ROS not only directly damage cell membranes, DNA, and protein; they also trigger formation of toxic cytokines and increase adhesion molecules leading to inflammatory responses, tissue damage, and multiple organ failure (1,10,17,41). Recently, growing evidence supports an important role of the mitochondrial permeability transition (MPT) in cell injury after IR (24,25,45,58). The mitochondrial membrane potential collapses when the MPT occurs, leading to failure of ATP synthesis, release of cytochrome c, and cell death (24,25,55). ROS cause opening of MPT pores (22...

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“…The induction of HO-1 also attenuates the development of hypertension and renal injury, leading to a decrease in angiotensin II-induced injury and salt-sensitive hypertension (Pradhan et al, 2006). Moreover, the induction of HO-1 before rapamycin treatment of transplant kidneys appears to limit the acute toxicity associated with rapamycin use (Gonçalves et al, 2006). Up-regulation of HO activity by gene transfer results in the normalization of blood pressure and increased expression of the antiapoptotic molecules Bcl-2, Bcl-xL, Akt, and pAkt in two-kidney one-clip renovascular hypertension .…”

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confidence: 99%