Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of the kidneys in heme metabolism was examined by determining heme oxygenase and biliverdin reductase activities in needle biopsy specimens from the kidneys of 11 female and 14 male patients with different renal diseases. The results show that both enzymes are present in human renal tissue. Our results indicate that heme oxygenase and biliverdin reductase increase slightly with age, but that there is no sex difference. A rising serum creatinine concentration is not reflected in the activity of heme degrading enzymes. Neither do the different types of nephritides, without detectable hemolysis, show significant differences in the renal activities of heme oxygenase and biliverdin reductase. This study thus outlines the basal physiological role of the human kidneys in heme degradation.
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PMID:Heme catabolism in human kidneys. Effect of various nephritides. 89 Sep 39

In renal failure serum bilirubin values are lower than normal. When renal failure is moderate this decrease is not due to a reduced-red-cell mass or to low levels of serum albumin. In splenic fine-needle aspirates from patients with renal failure, conditions for haem degradation were normal as indicated by normal activities of haem oxygenase and biliverdin reductase. Nor were the in vitro activities of these enzymes significantly depressed in the presence of ultrafiltrates of uraemic sera or of high concentrations of creatinine, urea or methylguanidine. The capacity of plasma from patients with renal failure to bind bilirubin was less than that of normal plasma, which at least partially explains the observed low values of serum bilirubin. There remains the possibility that in renal failure some bilirubin is removed from the plasma by a hitherto unknown route.
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PMID:Low serum bilirubin in chronic renal failure. Relation to haem metabolism. 125 56

Gold compounds are used clinically in rheumatoid arthritis therapy. Acute renal toxicity is observed in some patients receiving chrysotherapy. The present study addresses morphofunctional and biochemical changes in rat kidneys during the first 8 days following a single ip injection of gold sodium thiomalate (AuTM), one of the gold compounds presently in clinical use. Compared to controls, AuTM pretreatment resulted in increased urine output and elevated serum creatinine and urea nitrogen concentrations. Also, by Day 8, treated rats had decreased body weights and increased kidney weights. Postmortem examination on Day 1 showed pale and mottled kidneys and diffusely pale inner cortex. Microscopically, there was severe coagulative necrosis of the proximal tubular epithelium. Epithelial regeneration was prominent by Day 4 and was nearly complete by Day 8. The regenerating epithelium was hyperplastic with basophilic cytoplasm and pleomorphic nuclei. Alterations in renal heme biosynthesis and drug metabolism paralleled the morphologic changes. The activity of delta-aminolevulinic acid dehydratase and benzo[a]pyrene hydroxylase were inhibited on Days 1, 2, and 4 following AuTM administration. Decreases in monooxygenase activity were accompanied by decreases in renal cytochrome P-450 levels. In contrast, renal microsomal heme oxygenase activity was elevated 9.5-fold on Day 1 and 2.5-fold on Day 2. By Day 8, all renal enzymatic activities assayed for were similar to those obtained with untreated rats.
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PMID:Acute nephropathy induced by gold sodium thiomalate: alterations in renal heme metabolism and morphology. 311 10

25-Hydroxyvitamin D3 1 alpha- and 24-hydroxylase, NADPH-cytochrome c reductase, heme oxygenase, and ATPase activities were studied in viable kidney cells isolated from rats submitted to unilateral kidney damage (cortical electrocoagulation) and during the development of acute renal failure subsequent to excision of the contralateral undamaged kidney. Measurements of blood pH, plasma total and ionized calcium, phosphorus, creatinine, kidney histology, and phosphorus nuclear magnetic resonance spectroscopy determinations of phosphorus-containing compounds in kidney tissue were also performed. Seventy-two hours after unilateral kidney damage, no significant changes were observed in blood pH or in the plasma parameters studied. During this period, a significant increase in the activity of the 25-hydroxyvitamin D3 hydroxylases could be demonstrated in the cells of the contralateral undamaged kidney. A similar pattern of compensatory rise in the activity of the other enzymes studied was not detected. However, in the damaged kidney viable cells, the hydroxylase activities remained unchanged relative to those in sham-operated controls, despite a 5-fold increase in the inorganic phosphate content and a marked decrease in the organophosphorus and ATP content of this tissue. During the development of acute renal failure, a significant decrease in the activity of the hydroxylases occurred only when the rise in plasma creatinine concentration suggested severe renal insufficiency.
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PMID:Changes in 25-hydroxyvitamin D3 alpha- and 24-hydroxylase activities of kidney cells isolated from rats with either unilateral kidney damage or acute renal insufficiency. 622 3

Cellular content of heme is regulated by heme oxygenase, the rate limiting enzyme in the degradation of heme. Induction of heme oxygenase is a protective response in an in vivo model of heme protein mediated renal injury, the glycerol model of acute renal failure. In addition to heme, heme oxygenase is induced by diverse forms of oxidative stress, the functional significance of which is currently unknown. We examined whether heme oxygenase is induced, and the functional significance of such induction, in two in vivo models of oxidant-induced toxic nephropathy, namely, cisplatin and gentamicin nephropathies; nephrotoxicity in these models is not dependent on the delivery of a burden of heme proteins to the kidney as occurs in the glycerol model. We demonstrate induction of heme oxygenase mRNA and protein in the kidney as early as 6 and 12 hours after a single dose of cisplatin (6 mg/kg i.v.). Pretreatment with tin protoporphyrin, a competitive inhibitor of heme oxygenase, led to higher serum creatinine values on days 3 through 5 and lower inulin clearances on day 5; tin protoporphyrin also exacerbated renal injury in this model. Renal hemodynamics studied at day 2 after cisplatin demonstrate reduced renal blood flow rates, increased renal vascular resistance and increased fractional excretion of sodium in rats treated with tin protoporphyrin. Tin protoporphyrin alone had no significant effect on serum creatinine and renal hemodynamics in rats with intact, disease-free kidneys. We confirmed that tin protoporphyrin prevented the increase in heme oxygenase activity induced by cisplatin. Induction of heme oxygenase by cisplatin was associated with increased kidney heme content and ferritin content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of heme oxygenase in toxic renal injury: a protective role in cisplatin nephrotoxicity in the rat. 856 92

The role of oxidative stress in mercuric chloride (HgCl2)-induced nephrotoxicity is uncertain and controversial. We demonstrate that I.L.C-PK1 cells, exposed to HgCl2, generate massive amounts of hydrogen peroxide, the latter completely quenched by the hydrogen peroxide scavenger, pyruvate. HgCl2 exerts a dose-dependent cytotoxicity which is attenuated by pyruvate and catalase. Cellular generation of hydrogen peroxide arises, at least in part, from mitochondria since mitochondrial rates of generation of hydrogen peroxide increase in response to HgCl2; HgCl2 also provokes a shift in absorbance spectra in rhodamine 123 loaded-mitochondria and stimulates mitochondrial state 4 respiration. HgCl2, applied for one hour, impairs cellular vitality as demonstrated by the MTT assay, an assay dependent in part on mitochondrial function. HgCl2 impairs function in other organelles such as lysosomes that maintain a transmembrane proton gradient; these latter effects are partially attenuated by pyruvate. We complement these in vitro findings with in vivo evidence demonstrating that HgCl2 stimulates renal generation of hydrogen peroxide. The functional significance of such generation of hydrogen peroxide was evaluated in rats deficient in selenium and vitamin E, a nutrient deficiency that impairs the scavenging of hydrogen peroxide and promotes the toxicity of this oxidant. In these rats serum creatinine values were significantly higher on sequential days following the administration of HgCl2. To probe the renal response to oxidative stress induced by HgCl2, we examined hydrogen peroxide-scavenging enzymes and redox-sensitive genes. Catalase activity was unaltered whereas glutathione peroxidase activity was decreased, effects that may contribute to the net renal generation of hydrogen peroxide. The redox sensitive enzyme, heme oxygenase, was markedly up-regulated in the kidney in response to HgCl2. HgCl2 also induced members of the bcl family, bcl2 and bclx, genes that protect against apoptosis and oxidant injury. In another model of oxidant-induced renal injury, the glycerol model, bcl2 mRNA was not induced at 6 and 24 hours after the administration of glycerol. In summary, we demonstrate that HgCl2 potently stimulates renal generation of hydrogen peroxide in vitro and in vivo and such generation of peroxide contributes to renal dysfunction in vitro and in vivo. We also demonstrate that in response to HgCl2, redox sensitive genes are expressed including heme oxygenase and members of the bcl family.
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PMID:Renal oxidant injury and oxidant response induced by mercury. 887 81

Using an ultrapurified hemoglobin (Hb) solution, we investigated the physiological effects and cellular processing of Hb in rat kidneys and in cultured opossum kidney (OK) cells. Rats infused with < 5.0 g/kg Hb showed no change in baseline serum creatinine (SCr) values (0.58 +/- 0.05 mg/dl) over 48 h, whereas transient acute renal failure followed infusion of 7.5 g/kg Hb (SCr 3.4 +/- 1.02 mg/dl, P = 0.02). Histology of Hb-infused kidneys demonstrated tubular epithelial cell injury. Renal injury was not caused by volume or oncotic load, cardiovascular effect, or ATP depletion. After Hb infusion, heme oxygenase, the rate-limiting enzyme in Hb catabolism, was induced in an organ-specific fashion. Inhibiting heme oxygenase activity with cimetidine did not alter Hb renal injury. Using OK cells, we determined that renal epithelia process Hb by fluid-phase endocytosis. Proton permeability of fluorescein Hb endosomes was unaltered compared with fluorescein dextran controls, demonstrating that Hb does not alter endosomal membrane integrity. These data suggest that Hb renal injury in rats occurs following large doses of ultrapure Hb, does not alter early steps in Hb endosomal processing by renal epithelia, and involves a mechanism that is not heme oxygenase dependent.
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PMID:Interactions of ultrapure bovine hemoglobin with renal epithelial cells in vivo and in vitro. 924 90

Exogenous bilirubin (BR) substitutes for the protective effects of heme oxygenase (HO) in several organ systems. Our objective was to investigate the effects of exogenous BR in an in vivo model of ischemia-reperfusion injury (IRI) in the rat kidney. Four groups of male Sprague-Dawley rats were anesthetized using isoflurane in oxygen and treated with 1) 5 mg/kg intravenous (iv) BR, 1 h before ischemia and 6-h reperfusion; 2) vehicle 1 h before ischemia and 6-h reperfusion; 3) 20 mg/kg iv BR, 1 h before and during ischemia; and 4) vehicle 1 h before and during ischemia. Bilateral renal clamping (30 min) was followed by 6-h reperfusion. Infusion of 5 mg/kg iv BR achieved target levels in the serum at 6 h postischemia (31 +/- 9 micromol/l). Infusion of 20 mg/kg BR reached 50 +/- 22 micromol/l at the end of ischemia, and a significant improvement was seen in serum creatinine at 6 h (1.07 +/- 28 vs. 1.38 +/- 0.18 mg/dl, P = 0.043). Glomerular filtration rate, estimated renal plasma flow, fractional excretion of electrolytes, and renal vascular resistance were not significantly improved in BR-treated groups. Histological grading demonstrated a trend toward preservation of cortical proximal tubules in rats receiving 20 mg/kg iv BR compared with control; however, neither BR dose provided protection against injury to the renal medulla. At the doses administered, iv BR did not provide complete protection against IRI in vivo. Combined supplementation of both BR and carbon monoxide may be required to preserve renal blood flow and adequately substitute for the protective effects of HO in vivo.
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PMID:Intravenous bilirubin provides incomplete protection against renal ischemia-reperfusion injury in vivo. 1703 42

Radiocontrast agents are thought to induce acute kidney injury in part through increased production of reactive oxygen species and increased cellular apoptosis. In this study we determined whether heme oxygenase-1 could prevent or reduce radiocontrast-induced acute kidney injury and, if so, what were the mechanisms by which this can occur. Sodium iothalamate was administered to uninephrectomized, salt-depleted male Sabra rats to initiate acute kidney injury. Heme oxygenase-1 was induced with cobalt protoporphyrin or inhibited with stannous mesoporphyrin. Inhibition of heme oxygenase exacerbated kidney injury as measured by an increase in plasma creatinine and in superoxide production. Heme oxygenase-1 induction prevented the increase in plasma creatinine and in superoxide in both the cortex and medulla compared to untreated rats with acute kidney injury. This protective effect of heme oxygenase-1 was associated with increased anti-apoptotic proteins Bcl-2 and Bcl-xl and a decrease of pro-apoptotic caspase-3 and caspase-9 along with increased expression of inactive BAX. Our study suggests that increased levels of heme oxygenase-1 are protective against acute kidney injury due to radiocontrast exposure.
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PMID:Heme oxygenase-1 protects against radiocontrast-induced acute kidney injury by regulating anti-apoptotic proteins. 1791 15

Upregulating the heme oxygenase (HO) system removes the prooxidant heme, and thus is cytoprotective. Additionally, the products from the HO pathway including, carbon monoxide, bilirubin, and biliverdin, scavenge reactive oxygen species, inhibit lipid peroxidation, and suppress tissue inflammation, while the iron formed enhances the synthesis of the antioxidant ferritin. Deoxycorticosterone acetate (DOCA)-salt hypertension, a model of human primary aldosteronism, causes oxidative stress and impairs renal function by stimulating inflammatory/oxidative transcription factors such as NF-kappaB and activating protein (AP-1). The effect of the HO system in end-organ damage in mineralocorticoid-induced hypertension has not been fully characterized. In this study, the administration of the HO inducer hemin lowered blood pressure (191 vs. 135 mmHg; n = 22, P < 0.01), increased creatinine clearance, and reduced kidney hypertrophy proteinuria, albuminuria, and histopathological lesions, including glomerular hypertrophy, glomerulosclerosis, tubular dilation, tubular cast formation, and interstitial mononuclear cell infiltration in nephrectomy/DOCA-high-salt-hypertension. The renoprotection was accompanied by reduced levels of NF-kappaB, AP-1, fibronectin, transforming growth factor (TGF)-beta, and 8-isoprostane, a marker of oxidative stress. Correspondingly, a robust increase in total antioxidant capacity, HO activity, cGMP, and an antioxidant like ferritin was observed in hemin-treated animals. Our findings suggest that suppression of oxidative/inflammatory insults alongside the corresponding decline of fibronectin and TGF-beta, an activator of extracellular matrix proteins, may account for the attenuation of renal histopathological lesions and the antihypertrophic effects of hemin. The multifaceted interaction among the HO system, TGF-beta, fibronectin, AP-1, and NF-kappaB may be explored to design new drugs against end-stage-organ damage.
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PMID:Hemin therapy attenuates kidney injury in deoxycorticosterone acetate-salt hypertensive rats. 1911 43


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