UMLS:C0920646 - FACTA Search

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Query: UMLS:C0920646 (renal ischemia)
2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stressful stimuli such as heat, oxidative stress, heavy metals, and tissue trauma induce the expression of a family of proteins commonly referred to as stress proteins or heat shock proteins. The functions of these proteins are varied but include glycolysis, antioxidant defense, and several postulated "chaperone" functions involving the folding, unfolding, and translocation of other proteins. Heme oxygenase, the enzyme that catalyzes the degradation of heme to biliverdin, is also heat inducible and is, therefore, a heat shock protein. In the kidney, ischemia has been observed by several investigators to induce expression of the more commonly studied heat shock proteins HSP 70 and HSP 72. In addition, exposure of the kidney to myoglobin after glycerol injection induced heme oxygenase. The purpose of this study was to determine whether heme oxygenase is expressed as a stress protein after renal ischemia. Renal ischemia was induced in rats after right nephrectomy by clamping the renal artery for 40 minutes. Gene expression was evaluated after 60 minutes to 96 hours of postischemic reperfusion. There was essentially no expression of heme oxygenase at any of the time points evaluated. The absence of heme oxygenase expression was in striking contrast to the prompt and dramatic expression of HSP 70. This finding is consistent with the concept that all "stress proteins" are not equivalent and that, although there is considerable overlap between heat-sensitive gene promoters and oxidant stress-sensitive gene promoters, there is specificity for the type of stimulus that is able to activate any given stress protein gene.
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PMID:Heme oxygenase is not expressed as a stress protein after renal ischemia. 840 10

Presently we describe, for the first time, induction of microsomal heme oxygenase-1 (HO-1) mRNA and protein in response to ischemia/reperfusion and therefore define HO-1 as stress protein in the kidney. Specifically, Northern blot analysis of kidneys of rats subjected to bilateral ischemia for 30 min revealed an increase of 8- to 10-fold in the level of 1.8 Kb HO-1 mRNA 6 hr after reperfusion. The increase in transcript level was maintained when assessed after 24 hr. The levels of 1.3 and 1.9 Kb transcripts for the second isozyme of HO, HO-2, were decreased at both time points. The increase in HO-1 mRNA was reflected in HO-1 protein level, as judged by Western blot analysis and at the level of activity as judged by the rate of bilirubin formation. An absence of change in adrenal HO-1 mRNA level subsequent to renal ischemia/reperfusion suggested that the induction of kidney HO-1 did not reflect a generalized response of the rat organs to stress; rather, it was a target organ specific response. Moreover, in kidneys subjected to ischemia 6 and 24 hr after reperfusion, significant increases in the cellular content of heme were observed; heme is a known inducer of HO-1 synthesis. Ischemia/reperfusion also adversely affected concentration of cytochrome P-450 in both mitochondrial and the microsomal fractions of the kidney. We suggest that increase in tissue heme levels may be a significant factor in damage caused by ischemia/reperfusion to renal tissue, whereby the metalloporphyrin promotes oxygen-free radical formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of kidney heme oxygenase-1 (HSP32) mRNA and protein by ischemia/reperfusion: possible role of heme as both promotor of tissue damage and regulator of HSP32. 842 44

For the first time, the authors report an intimate link between kidney and heart functions as it pertains to the regulation of stress protein gene expression in the heart. They show that the stress on the target organ, the kidney, is translated into a response in the cardiovascular system, as reflected by the induction of heme oxygenase (HO)-1 gene expression, which, in turn, may be a cellular defense response as suggested by an increase in cGMP level in the heart, and an increase in the rate of bilirubin formation by the kidney and the heart. HO-1 is a stress protein (HSP32) and, together with HO-2, catalyzes oxidation of the heme molecule to generate CO, a likely signal molecule for the generation of cGMP, and bilirubin, an antioxidant. Specifically, bilateral renal ischemia for 30 min caused a 3-fold increase in the approximately 1.8-kb HO-1 mRNA in the heart within 4 h after reperfusion and remained essentially at this level for 24 h, at which point, a 2.6-fold increase in HO-1 mRNA in the descending aorta was also detected. Heart HO-1 mRNA remained elevated for more than 48 h; in contrast, at the 48-h time point, the transcript level in the kidney, which had increased by 10-fold 24 h after reperfusion, had returned to the control level. Neither in the heart nor in the kidney did HO-2 transcripts (approximately 1.3 and 1.9 kb) respond to renal ischemia/ reperfusion. The increase in heart HO-1 transcript level was accompanied by an increase in HO-1 protein, as judged by Western blot and immunohistochemical analysis, and in enzyme activity, as judged by bilirubin formation. In addition, cGMP concentration in the heart was elevated when measured at 24 h and 48 h after reperfusion of the kidney, in the absence of an increase in the activity of NO. Data suggest that hemodynamic stress caused by the occlusion of the renal artery is responsible for activation of HO-1 gene expression in the heart. An argument is made for the role of HO-1 in the defense mechanisms of the heart pertaining to the enzyme's function in a hemoprotein regulatory capacity, along with the biological activity of its products.
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PMID:Renal ischemia/reperfusion up-regulates heme oxygenase-1 (HSP32) expression and increases cGMP in rat heart. 866 53

In mammals the rate-limiting step in heme catabolism is the heme oxygenase (HO) system. Two isozymes, HO-1 and HO-2, oxidatively cleave the substrate to form biliverdin, and the potential cellular messenger, CO; the chelated iron is released as the result of the tetrapyrrole ring opening. Biliverdin is subsequently reduced to bilirubin, an antioxidant, by biliverdin reductase. The aim of the present study was to investigate the involvement of HO-1, a heat shock/stress protein, in protection offered by the spin trap agent, N-tert-butyl-alpha-phenyl-nitrone (PBN), against kidney ischemia/reperfusion injury. For this, HO-1 expression and assessment of the parameters associated with tissue-oxidative injury were compared in the presence or absence of PBN pretreatment of rats (100 mg/kg i.p., 30 min) before the onset of 30-min ischemia. Twenty-four hours after reperfusion, Northern blot analysis showed an unprecedented approximately 37-fold increase in 1.8-kb HO-1 mRNA in PBN pretreated rat kidney; HO-2 mRNA levels did not increase. At 48 h, the levels of HO-1 mRNA remained nearly 14-fold higher than the control value. In the absence of PBN, the levels measured approximately 5- and 2-fold higher than control values at the 24- and 48-h intervals, respectively. PBN pretreatment also resulted in a most impressive increase in the levels of HO-1 protein as judged by Western blot analysis and measurement of enzyme activity at the 24-h time point. As detected by immunohistochemical analysis, PBN pretreatment caused an increase in HO-1 and biliverdin reductase-immunoreactive proteins in the cortex and in the outer stripe of the outer medulla. In the absence of PBN pretreatment, there was an intense immunostaining for HO-1 in the medullary rays, which corresponded with iron and lipid peroxidation staining of the region; these observations were not made with PBN-pretreated kidneys. Collectively, the findings are consistent with the likelihood that suprainduction of HO-1 gene expression protects the kidney from free radical-mediated injury by increasing the capacity to produce the potent cellular antioxidant bilirubin. We also suggest spin trap-mediated protection against ischemia/reperfusion injury is likely due to a sustained elevation of HO-1 gene expression by formation of stable radicals.
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PMID:Spin trap (N-t-butyl-alpha-phenylnitrone)-mediated suprainduction of heme oxygenase-1 in kidney ischemia/reperfusion model: role of the oxygenase in protection against oxidative injury. 1052 16

Oxygen tensions in the kidney are heterogeneous, and their changes presumably play an important role in renal physiologic and pathophysiologic processes. A family of hypoxia-inducible transcription factors (HIF) have been identified as mediators of transcriptional responses to hypoxia, which include the regulation of erythropoietin, metabolic adaptation, vascular tone, and neoangiogenesis. In vitro, the oxygen-regulated subunits HIF-1alpha and -2alpha are expressed in inverse relationship to oxygen tensions in every cell line investigated to date. The characteristics and functional significance of the HIF response in vivo are largely unknown. High-amplification immunohistochemical analyses were used to study the expression of HIF-1alpha and -2alpha in kidneys of rats exposed to systemic hypoxia bleeding anemia, functional anemia (0.1% carbon monoxide), renal ischemia, or cobaltous chloride (which is known to mimic hypoxia). These treatments led to marked nuclear accumulation of HIF-1alpha and -2alpha in different renal cell populations. HIF-1alpha was mainly induced in tubular cells, including proximal segments with exposure to anemia/carbon monoxide, in distal segments with cobaltous chloride treatment, and in connecting tubules and collecting ducts with all stimuli. Staining for HIF-1alpha colocalized with inducible expression of the target genes heme oxygenase-1 and glucose transporter-1. HIF-2alpha was not expressed in tubular cells but was expressed in endothelial cells of a small subset of glomeruli and in peritubular endothelial cells and fibroblasts. The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of HIF-1alpha and HIF-2alpha is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles. The expression of HIF-2alpha in peritubular fibroblasts suggests a role in erythropoietin regulation.
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PMID:Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. 1208 96

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 microM 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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PMID:Functional activation of heat shock factor and hypoxia-inducible factor in the kidney. 1213 41

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

In human and murine models of sickle cell disease (SCD), heme oxygenase-1 (HO-1) is induced in the kidney, an organ commonly involved in SCD. The present study assessed the role of HO-1 by using a competitive inhibitor of HO activity, tin protoporphyrin (SnPP), in protocols affording a composite, clinically relevant analysis of the kidney in SCD under unstressed and stressed conditions. Whereas short-term administration of SnPP exerted comparable renal hemodynamic effects in wild-type and sickle mice, chronic administration of SnPP exerted divergent effects: SnPP provoked tubulointerstitial inflammation and up-regulation of injury-related genes in wild-type mice, whereas in sickle mice SnPP reduced expression of injury-related genes and vascular congestion without provoking tubulointerstitial inflammation. SnPP also protected against the heightened sensitivity to renal ischemia observed in sickle mice, preventing ischemia-induced worsening of renal injury in sickle mice above that observed in wild-type mice. Effective and comparable inhibition of HO activity by SnPP in wild-type and sickle mice was confirmed. These findings suggest that induction of HO-1, at least as assessed by this approach, may contribute to renal injury in this murine model of SCD and uncover an experimental maneuver that protects the kidney in murine SCD.
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PMID:Anomalous renal effects of tin protoporphyrin in a murine model of sickle cell disease. 1681 58

Bradykinin B1 receptors are exclusively expressed in inflamed tissues. For this reason, they have been related with the outcomes of several pathologies. Ischemia-reperfusion injury is caused by the activation of inflammatory and cytoprotective genes, such as macrophage chemoattractant protein-1 and heme oxygenase-1, respectively. This study was aimed to analyze the involvement of bradykinin B1 and B2 receptors (B1R and B2R) in tissue response after renal ischemia-reperfusion injury. For that, B1R (B1-/-), B2R (B2-/-) knockout animals and its control (wild-type mice, B1B2+/+) were subjected to renal bilateral ischemia, followed by 24, 48 and 120 h of reperfusion. At these time points, blood serum samples were collected for creatinine and urea dosages. Kidneys were harvested for histology and molecular analyses by real-time PCR. At 24 and 48 h of reperfusion, B1-/- group resulted in the lowest serum creatinine and urea levels, indicating less renal damage, which was proved by renal histology. Renal protection associated with B1-/- mice was also related with higher expression of HO-1 and lower expression of MCP-1. In conclusion, the absence of B1R had a protective role against inflammatory responses developed after renal ischemia-reperfusion injury.
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PMID:Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia-reperfusion injury. 1716 49

Statins induce heme oxygenase-1 (HO-1) in several cell types, such as vascular smooth muscle cells, endothelial cells, and macrophages. The present study assessed the role of statin-induced HO-1 up-regulation on circulating monocytes/macrophages and their contribution in preventing renal ischemia-reperfusion (IR) injury in a rat model. Cerivastatin was administered via gavage (0.5 mg/kg) for 3 days before IR injury; controls received vehicle. Statin pretreatment reduced renal damage and attenuated renal dysfunction (P < 0.05) after IR injury. The protective statin pretreatment effect was completely abolished by cotreatment with tin protoporphyrin IX (Sn-PP), a competitive HO inhibitor. IR increased HO-1 expression at the transcript and protein level in renal tissue. This effect was significantly more evident (P < 0.05) in the statin-pretreated animals 24 hours after IR injury. We identified infiltrating macrophages as the major source of tissue HO-1 production. Moreover, in ancillary cell culture (monocyte cell line) and in in vivo experiments (isolation of circulating monocytes), we confirmed that statins regulate HO-1 expression in these cells. We conclude that statin treatment up-regulates HO-1 in circulating monocytes/macrophages in vivo and in vitro. We hypothesize that local delivery of HO-1 from infiltrating macrophages exerts anti-inflammatory effects after IR injury and thereby may reduce tissue destruction.
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PMID:Statins attenuate ischemia-reperfusion injury by inducing heme oxygenase-1 in infiltrating macrophages. 1739 59

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