Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although reactive oxygen species are believed to participate in postischemic renal injury, the actual chemical species involved and the role of endogenous scavenging systems in protecting against injury requires additional study. Hydrogen peroxide, which derives from superoxide radical, is toxic and also yields toxic hydroxyl radical. 3-amino-1,2,4-triazole reacts with catalase to form irreversibly inactivated catalase only in the presence of hydrogen peroxide. We made use of this chemical reaction both to determine whether inhibition of the hydrogen peroxide-scavenging enzyme catalase would influence ischemic renal injury and to measure hydrogen peroxide production rates after ischemia. Sprague-Dawley rats were given aminotriazole (100 mg/kg) one hour before 40 min of renal ischemia. Twenty-four h after ischemia GFR had decreased to 300 microL/min in control animals and to 50 microL/min in aminotriazole-treated animals. Histologic evidence of injury was also worse in catalase-inhibited animals. To measure hydrogen peroxide production rates aminotriazole was given 60 min before measurement of renal catalase activity. In control animals, aminotriazole caused a 53.4% decrease in catalase activity. In animals subjected to 40 min of ischemia plus either 10 or 60 min of reflow catalase activity decreased by 33.9 and 49.5% (not significantly different from control). Thus, when measured by this method total renal hydrogen peroxide production was considerable but was not increased by ischemia. However, in isolated proximal tubule segments 60 min of anoxia and 30 min of reoxygenation caused a 42% increase in H2O2 released into the incubation medium. In summary, inhibition of catalase before ischemia led to exacerbation of ischemic injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hydrogen peroxide and ischemic renal injury: effect of catalase inhibition. 164 49

To investigate the functional role of renal intrinsic antioxidant enzymes (AOEs), the levels of AOE activities in isolated glomeruli and the changes in renal function to oxidant insults were assessed in normal control rats (NC, N = 23) and rats subjected to 30-minutes of complete renal ischemia for three days (day-3, N = 20) or six days (day-6, N = 23) prior to study. When compared to NC, the activities of total and manganese (cyanide-insensitive) superoxide dismutase, glutathione peroxidase, and catalase were increased more than twofold in day-6 animals, on average, from 36 +/- 4 U/mg protein, 9 +/- 1 U/mg protein, 129 +/- 21 U/mg protein and 1.32 +/- 0.20 k/mg protein, respectively, to 80 +/- 5, 27 +/- 3, 283 +/- 41 and 3.20 +/- 0.20, respectively (P less than 0.05 for all). There were no changes in AOE activities in day-3 animals. In day-6 animals, however, the activities of non-AOEs, LDH and fumarase were found to be unaffected. Separate groups of NC (N = 12), day-3 (N = 5) and day-6 (N = 12) rats were subjected to either 30 minutes of ischemia plus 60 minutes of reperfusion (I/R) or unilateral i.a. infusion of hydrogen peroxide (H2O2, 35 mu moles in 1 hr). The degree of reduction in inulin and para-amino hippurate clearance rates following I/R were significantly less in day-6 (-21 +/- 3% and -12 +/- 2, respectively) compared to NC (-69 +/- 9% and -59 +/- 11, respectively) or day-3 rats (-73 +/- 7% and -62 +/- 10, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of intrinsic antioxidant enzymes in renal oxidant injury. 240 19

The occurrence of focal fibrinoid necrosis of capillary loops in the very early stages of ANCA-associated necrotizing crescentic glomerulonephritis (NCGN) and the increased prevalence of this disease at older age suggest that renal ischemia may play an additional role in its pathophysiology. In the present study we investigated the contribution of renal ischemia to the induction of anti-myeloperoxidase (MPO) associated NCGN in a previously described rat model of this disease. The development of renal lesions is dependent on the presence of an anti-MPO immune response and the localization of a lysosomal extract containing lytic enzymes and MPO in combination with hydrogen peroxide (H2O2) along the glomerular basement membrane (GBM). The hypothesis tested whether perfusion of hydrogen peroxide (H2O2) could be replaced by ischemia/reperfusion (I/R) injury, as I/R injury activates endothelial cells to produce oxygen metabolites. I/R was induced by clamping the renal artery for 20 minutes in kidneys in which the circulation had been restored several minutes after perfusion with the lysosomal extract in MPO immunized rats. Rats developed lesions characterized by intra- and extracapillary cell proliferation, periglomerular infiltration, ruptures in Bowman's capsule, ischemic tubuli, and interstitial mononuclear infiltrate. Immune deposits, however, persisted for a longer time along the GBM after perfusion of lytic enzymes followed by I/R injury compared to previous studies in which H2O2 in conjunction with lytic enzymes were perfused in MPO-immunized rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal ischemia/reperfusion injury contributes to renal damage in experimental anti-myeloperoxidase-associated proliferative glomerulonephritis. 778 9

Reactive oxygen species (ROS) have been implicated in the pathophysiology of renal ischemia/reperfusion injury. Endothelin-1 (ET-1) is generated in abundance in renal ischemia/reperfusion with resultant decreases in renal blood flow and glomerular filtration rate. To determine if ROS regulate ET-1 production, the effect of ROS donors or scavengers on ET-1 protein and mRNA levels in cultured human mesangial cells was examined. Incubation with xanthine/xanthine oxidase, glucose oxidase, or H2O2 caused a dose-dependent rise in ET-1 release. Similarly, xanthine/xanthine oxidase or H2O2 augmented ET-1 mRNA levels. In contrast, the ROS scavengers dimethylthiourea (DMTU), dimethylpyrroline N-oxide, or pyrrolidine dithiocarbamate reduced basal ET-1 release, while DMTU lowered ET-1 mRNA levels. Deferoxamine, an iron chelator, also decreased basal ET-1 release. Superoxide dismutase potentiated the ET-1 stimulatory effect of xanthine/xanthine oxidase, while catalase abrogated the effect of xanthine/xanthine oxidase and H2O2. The effects of ROS were unrelated to changes in nitric oxide production or cytotoxicity. These data indicate that exogenously or endogenously-derived ROS can increase ET-1 production by human mesangial cells. While superoxide anion reduces ET-1 levels, H2O2 leads to enhanced production of the peptide. ROS stimulation of mesangial cell ET-1 production may contribute to impaired glomerular hemodynamics in the setting of renal ischemia/reperfusion injury.
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PMID:Effect of reactive oxygen species on endothelin-1 production by human mesangial cells. 877 Sep 66

21-Aminosteroids have incited a great deal of interest owing to its ability to inhibit lipid peroxidation and prevent organ damage. The main mechanism by which 21-aminosteroids inhibit lipid peroxidation is similar to the naturally occurring chain-breaking antioxidant alpha-tocopherols. Therefore, to determine whether 21-aminosteroids offer any advantage over alpha-tocopherol, we compared their effects on an in vivo and in vitro models of renal injury. 21-Aminosteroid (U-74006 F) at 3 mg/kg or alpha-tocopherol succinate at 10 mg/kg was administered intravenously once before bilateral renal ischemia and again before reperfusion. Acute administration 21-aminosteroid but not alpha-tocopherol, was attended by suppression of ischemia reperfusion-induced renal lipid peroxidation and injury. However, 4 weeks of dietary enrichment of rats with alpha-tocopherol (1000 IU/kg) was effective in suppressing these ischemia reperfusion-induced changes. In cell culture system, concurrent presence of 21-aminosteroid but not alpha-tocopherol abrogated H2O2-induced renal epithelial lipid peroxidation and injury. However, alpha-tocopherol was completely effective when cells were incubated with it for 14 h. Further, only the cells incubated with vitamin E for 14 h-but not for 1 or 3 h-had a significant increase in vitamin E content, which suggests that a delay in prompt cellular up take of vitamin E may explain its lack of acute effects. Thus, unlike alpha-tocopherol, 21-aminosteroid appears readily and completely available for its chain-breaking antioxidant activity both in vitro and in vivo. 21-Aminosteroids may, therefore, offer a therapeutic advantage over alpha-tocopherols in acute injury settings.
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PMID:Comparative study of the effect of 21-aminosteroid and alpha-tocopherol on models of acute oxidative renal injury. 889 71

Reactive oxygen species (ROS) contribute to the ischemia-reperfusion injury. In kidney, the intracellular sources of ROS during ischemia-reperfusion are still unclear. In the present study, we investigated the role of the catecholamine-degrading enzyme monoamine oxidases (MAOs) in hydrogen peroxide (H2O2) generation after reperfusion and their involvement in cell events leading to tissue injury and recovery. In a rat model of renal ischemia-reperfusion, we show concomitant MAO-dependent H2O2 production and lipid peroxidation in the early reperfusion period. Rat pretreatment with the irreversible MAO inhibitor pargyline resulted in the following: i) prevented H2O2 production and lipid peroxidation; ii) decreased tubular cell apoptosis and necrosis, measured by TUNEL staining and histomorphological criteria; and iii) increased tubular cell proliferation as determined by proliferating cell nuclear antigen expression. MAO inhibition also prevented Jun N-terminal kinase phosphorylation and promoted extracellular signal-regulated kinase activation, two mitogen-activated protein kinases described as a part of a "death" and "survival" pathway after ischemia-reperfusion. This work demonstrates the crucial role of MAOs in mediating the production of injurious ROS, which contribute to acute apoptotic and necrotic cell death induced by renal ischemia-reperfusion in vivo. Targeted inhibition of these oxidases could provide a new avenue for therapy to prevent renal damage and promote renal recovery after ischemia-reperfusion.
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PMID:Regulation of JNK/ERK activation, cell apoptosis, and tissue regeneration by monoamine oxidases after renal ischemia-reperfusion. 1203 44

To ascertain the role of spermidine/spermine N-1-acetyl-transferase (SSAT; the rate-limiting enzyme in polyamine catabolism) in cell injury, cultured kidney (HEK 293) cells conditionally overexpressing SSAT were generated. The SSAT expression was induced and its enzymatic activity increased 24 h after addition of tetracycline and remained elevated over the length of the experiments. Induction of SSAT upregulated the expression of polyamine oxidase and resulted in the reduction of cellular concentration of spermidine and spermine, increased concentration of putrescine, and inhibited cell growth. SSAT overexpression increased the expression of heme oxygenase-1 (HO-1) by 350% 24 h after addition of tetracycline, indicating the induction of oxidative stress. The presence of catalase significantly prevented the upregulation of HO-1 in SSAT overexpressing cells, indicating that generation of H2O2 is partially responsible for the induction of oxidative stress. Overexpression of SSAT caused rounding and loss of cell anchorage and significantly altered the morphology of actin-containing filopodia, suggesting an adhesion defect. SSAT upregulation may mediate majority of the oxidative stress in kidney ischemia-reperfusion injury (IRI) as manifested by decreased cell growth, generation of toxic metabolites (H2O2 and putrescine), upregulation of HO-1, disruption of cell anchorage, and defect in cell adhesion. These data point to the inhibition of polyamine catabolism as a therapeutic approach for the prevention of tissue injury in kidney IRI.
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PMID:Overexpression of SSAT in kidney cells recapitulates various phenotypic aspects of kidney ischemia-reperfusion injury. 1521 72

Renal ischemia-reperfusion (IR) injury is a major clinical problem without effective therapy. We recently reported that volatile anesthetics protect against renal IR injury, in part, via their anti-inflammatory properties. In this study, we demonstrate the anti-inflammatory and antinecrotic effects of sevoflurane in cultured kidney proximal tubule cells and probed the mechanisms of sevoflurane-induced renal cellular protection. To mimic inflammation, human kidney proximal tubule (HK-2) cells were treated with tumor necrosis factor-alpha (TNF-alpha; 25 ng/ml) in the presence or absence of sevoflurane. In addition, we studied the effects of sevoflurane pretreatment on hydrogen peroxide (H2O2)-induced necrotic cell death in HK-2 or porcine proximal tubule (LLC-PK1) cells. We demonstrate that sevoflurane suppressed proinflammatory effects of TNF-alpha evidenced by attenuated upregulation of proinflammatory cytokine mRNA (TNF-alpha, MCP-1) and ICAM-1 protein and reduced nuclear translocation of the proinflammatory transcription factors NF-kappaB and AP-1. Sevoflurane reduced necrotic cell death induced with H2O2 in HK-2 cells as well as in LLC-PK1 cells. Sevoflurane treatment resulted in phosphorylation of prosurvival kinases, ERK and Akt, and increased de novo HSP-70 protein synthesis without affecting the synthesis of HSP-27 or HSP-32. We conclude that sevoflurane has direct anti-inflammatory and antinecrotic effects in vitro in a renal cell type particularly sensitive to injury following IR injury. These mechanisms may, in part, account for volatile anesthetics' protective effects against renal IR injury.
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PMID:Anti-inflammatory and antinecrotic effects of the volatile anesthetic sevoflurane in kidney proximal tubule cells. 1647 75

Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H2O2) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21(WAF1/CiP1) (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H2O2 rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H2O2-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.
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PMID:ATF3 protects against renal ischemia-reperfusion injury. 1823 2

Heat shock proteins (Hsps) are protective in models of transplantation, yet practical strategies to upregulate them remain elusive. The heat shock protein 90-binding agent (HBA) geldanamycin and its analogs (17-AAG and 17-DMAG) are known to upregulate Hsps and confer cellular protection but have not been investigated in a model relevant to transplantation. We examined the ability of HBAs to upregulate Hsp expression and confer protection in renal adenocarcinoma (ACHN) cells in vitro and in a mouse model of kidney ischemia-reperfusion (I/R) injury. Hsp70 gene expression was increased 30-40 times in ACHN cells treated with HBAs, and trimerization and DNA binding of heat shock transcription factor-1 (HSF1) were demonstrated. A three- and twofold increase in Hsp70 and Hsp27 protein expression, respectively, was found in ACHN cells treated with HBAs. HBAs protected ACHN cells from an H2O2-mediated oxidative stress, and HSF1 short interfering RNA was found to abrogate HBA-mediated Hsp induction and protection. In vivo, Hsp70 was upregulated in the kidneys, liver, lungs, and heart of HBA-treated mice. This was associated with a functional and morphological renal protection from I/R injury. Therefore, HBAs mediate upregulation of protective Hsps in mouse kidneys which are associated with reduced I/R injury and may be useful in reducing transplant-associated kidney injury.
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PMID:Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia-reperfusion injury. 1856 31


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