The Role of Growth Factors on Renal Tubular Cells Submitted to Hypoxia and Deprived of Glucose

Durão, Marcelino de Souza; Razvickas, Clara Versolato; Gonçalves, Elsa Alídia Petry; Okano, Ryo; Camargo, Simone M. R.; Monte, Julio Cesar Martins; Santos, Oscar Fernando Pavão dos

doi:10.1081/jdi-120021149

Cited by 22 publications

(9 citation statements)

References 15 publications

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“…The absence of the effect of hypoxia-reoxygenation without glucose deprivation may indicate that the cells adapted to hypoxia by partially switching to glycolysis. Our data are consistent with the recent study by de Souza Durao et al (11), which also used a glucose-free medium to induce hypoxia in cultured renal tubular epithelial cells. The exposure of cells to hypoxia-reoxygenation did not decrease but rather increased sphingomyelin content, suggesting little contribution of sphingomyelinases to ceramide generation.…”

Section: Discussionsupporting

confidence: 83%

Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia-reoxygenation

Basnakian¹,

Ueda²,

Hong³

et al. 2005

American Journal of Physiology-Renal Physiology

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. Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia reoxygenation. Am J Physiol Renal Physiol 288: F308 -F314, 2005. First published October 12, 2004 doi:10.1152/ajprenal.00204.2004.-Ceramide is known to play a role in the cell signaling pathway involved in apoptosis. Most studies suggest that enhanced ceramide generation is the result of hydrolysis of sphingomyelin by sphingomyelinases. However, the role of ceramide synthase in enhanced ceramide generation has not been previously examined in hypoxia-reoxygenation injury. In the present study, we demonstrated that 60-min hypoxia of rat renal tubular epithelial NRK-52E cells in a gas chamber with 95% N2-5% CO2 with glucose deprivation resulted in a significant increase in ceramide generation. The ceramide level further increased after reoxygenation for 60 min. Exposure of cells to hypoxia-reoxygenation resulted in a significant increase in ceramide synthase activity without any significant change in acid or neutral sphingomyelinase. The hypoxia-reoxygenation of NRK-52E cells was also associated with the release of endonuclease G (EndoG) from mitochondria to cytoplasm measured by Western blot analysis and endonuclease activity assay. It further led to the fragmentation of DNA and cell death. A specific inhibitor of ceramide synthase, fumonisin B1 (50 M), suppressed hypoxia-reoxygenationinduced ceramide generation and provided protection against hypoxia-reoxygenation-induced EndoG release, DNA fragmentation, and cell death. Taken together, our data suggest that hypoxia-reoxygenation results in an activation of ceramide synthase rather than sphingomyelinase and that ceramide synthase-dependent ceramide generation is a key modulator of EndoG-mediated cytotoxicity in hypoxiareoxygenation injury to renal tubular epithelial cells. kidney; NRK-52E cells; fumonisin B1; endonuclease G; DNA fragmentation BOTH HYPOXIA-REOXYGENATION of renal cells in vitro and kidney ischemia-reperfusion injury in vivo are strongly associated with cell death (3). Ceramide, a metabolite of sphingolipids, participates in cell death signaling pathways (16,17,22). Although the role of ceramide has been studied in apoptotic cell death in response to a variety of stimuli, there is limited information of a role of ceramide in hypoxia-reoxygenation injury. In vivo studies of ischemic injury to the kidney (39, 40) or brain (19) as well as in vitro study of hypoxic injury to cultured PC12 cells (37) have shown an increase in ceramide level. However, the cause-effect relationship between an alteration of ceramide and cytotoxicity is not known in hypoxiareoxygenation injury to renal tubular epithelial cells, and the pathways for ceramide generation in ischemia-reperfusion or hypoxia-reoxygenation injury remain to be elucidated.Ceramide is generated by the two major pathways: condensation of sphingosine or sphinganine and fatty acyl-CoA by ceramide synthase or by hydrolysis of sphingomyelin by sphingomyelinases (16,17,22). Several studies...

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Section: Discussionsupporting

confidence: 83%

Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia-reoxygenation

Basnakian¹,

Ueda²,

Hong³

et al. 2005

American Journal of Physiology-Renal Physiology

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“…Indeed, a survival activity has been documented for bFGF, PDGF-B, VEGF, nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and erythropoietin for hypoxic neurons (15,(35)(36)(37)(38)(39)(40)(41), acidic fibroblast growth factor, IGF-I and erythropoietin for hypoxic myocardial cells (42)(43)(44)(45)(46), VEGF for hypoxic chondrocytes (47), or hepatocyte growth factor and erythropoietin for hypoxic renal cells (48,49). Growth factors may also protect cells against apoptosis in response to other stimuli, as exemplified by the ability of erythropoietin, c-kit ligand, or interleukin-3 to block p53-mediated apoptosis of hematopoietic cell lines (50 -52) by the protective effect of IGF-I or EGF on epithelial cells or lymphocytes against Fas-induced apoptosis (53)(54)(55) or by the inhibition by IGF-I of glutamateinduced apoptosis of oligodendrocyte progenitors (56).…”

Section: Discussionmentioning

confidence: 99%

A Novel Role for Vascular Endothelial Growth Factor as an Autocrine Survival Factor for Embryonic Stem Cells during Hypoxia

Brusselmans

Bono

Collen

et al. 2005

Journal of Biological Chemistry

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Vascular endothelial growth factor (VEGF) is best known for its angiogenic activity on endothelial cells, but it also affects neurons, pneumocytes, and other mature cell types as well as endothelial, neural, and hematopoietic progenitors. Here, we examined its effect on pluripotential embryonic stem (ES) cells under hypoxic stress. ES cells were found to produce VEGF and to express VEGF receptor-2 and neuropilin-1 (Nrp-1), a VEGF 165 isoform-specific receptor. During hypoxia, expression levels of VEGF, Flk-1, and Nrp-1 were elevated. Inhibition or targeted gene inactivation of VEGF increased ES cell apoptosis during prolonged hypoxia (48 h) by about 10-fold. The survival activity of VEGF was specific since inhibition of other growth factors (including basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor, platelet-derived growth factor, and placental growth factor) had no effect. Neuropilin-1 was involved in the VEGF-survival activity since overexpression of Nrp-1 decreased hypoxiainduced apoptosis about 3-fold. The hypoxia-response element, via which hypoxia-inducible transcription factors up-regulate VEGF expression under hypoxic conditions, was critical since targeted deletion of this element in the VEGF promoter enhanced hypoxia-induced ES cell apoptosis to the same extent as VEGF inhibition or gene inactivation. Thus, VEGF plays a critical role in survival of ES cells during prolonged hypoxia.

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“…Using the DNA-reactive dyes with different penetration through the plasma membrane, we differentiated the living, necrotic, and apoptotic cells by staining with acridine orange, ethidium bromide, and Hoechst 33342, respectively. 16,17 Cerebellar granule cells were transferred to the 0.01 mmol/L glycine-supplemented BSS omitting MgCl 2 . Control cells were incubated in the medium for 2 h. Influence of SP on cells was studied after 2 h of preincubation in the medium with SP.…”

Section: Estimation Of Neuronal Damage After Glutamate Excitotoxic Acmentioning

confidence: 99%

Phosphono Analogues of 2‐Oxoglutarate Protect Cerebellar Granule Neurons upon Glutamate Excitotoxicity

Bunik

Kabysheva

Klimuk

et al. 2009

Annals of the New York Academy of Sciences

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Glutamate excitotoxicity is an important contributor to neuronal loss. Glutamate-induced Ca(2+) deregulation and accompanying mitochondrial depolarization are closely associated with the onset of apoptotic and necrotic neuronal death. We investigated the role in these phenomena of 2-oxoglutarate dehydrogenase (OGDH), the enzyme participating in mitochondrial degradation of glutamate. To achieve this goal, we used specific effectors of cellular OGDH, succinyl phosphonate and its phosphonoethyl ether. Preincubation of cerebellar granule neurons with these phosphono analogues of 2-oxoglutarate was shown to protect the cells from glutamate-induced Ca(2+) deregulation and irreversible mitochondrial depolarization, followed simultaneously by fluorescence of fura-2FF and rhodamine 123, respectively. The protection was characterized by delay in onset and decreased propagation of Ca(2+) deregulation and by reversibility of the associated mitochondrial depolarization. Compared to its phosphonoethyl ether, succinyl phosphonate exhibited both higher affinity to OGDH in vitro and better protection from Ca(2+) deregulation in situ, supporting the assumption that neuroprotection by phosphonates involves their interaction with cellular OGDH. Preincubation of cerebellar granule neurons with succinyl phosphonate decreased neuronal death after excitotoxic action of glutamate. Thus, specific inhibitors of OGDH alleviate glutamate-induced calcium deregulation, mitochondrial depolarization, and neuronal death.

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The Role of Growth Factors on Renal Tubular Cells Submitted to Hypoxia and Deprived of Glucose

Abstract: HGF decreases cell death on MDCK cells after hypoxic-induced injury, probably acting in both necrotic and apoptotic mechanisms.

Cited by 22 publications

References 15 publications

Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia-reoxygenation

Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia-reoxygenation

A Novel Role for Vascular Endothelial Growth Factor as an Autocrine Survival Factor for Embryonic Stem Cells during Hypoxia

Phosphono Analogues of 2‐Oxoglutarate Protect Cerebellar Granule Neurons upon Glutamate Excitotoxicity

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