Iron, heme oxygenase, and glutathione: Effects on myohemoglobinuric proximal tubular injury

Zager, Richard A.; Burkhart, Kirstin M.; Conrad, D S; Gmur, Dennis J.

doi:10.1038/ki.1995.457

Cited by 126 publications

(84 citation statements)

References 20 publications

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“…Upregulation of HO-1 has been shown to diminish formation of vascular heme and O 2 Ϫ , increase extracellular superoxide dismutase in diabetic rats (30,46), and increase reduced glutathione (47). Acute and chronic nephropathies also are related to the elevation of cellular heme protein, such as that seen in sickle cell anemia and hemolysis (44,48). Furthermore, an increase in cellular heme results in elevation of gp91 (NOX4)-mediated superoxide formation (49).…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Goodman¹,

Chander²,

Rezzani³

et al. 2006

Journal of the American Society of Nephrology

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Heme oxygenase-1 (HO-1) and -2 play an important role in cytoprotection and are physiologic regulators of heme-dependent protein synthesis in renal tissues. The impact of HO-2 deletion comparing hyperglycemic HO-2 (؉/؉) mice and HO-2 knockout (؊/؊) mice was examined. Hyperglycemia was induced by streptozotocin (STZ) injection, and its effect on renal HO-1/HO-2 protein, HO activity, and creatinine levels were assessed. The effect of HO induction using systemic administration of the HO inducers heme or cobalt protoporphyrin and the effect of HO inhibition using systemic administration of the HO inhibitor tin mesoporphyrin also were assessed in STZ-treated mice. In STZ-treated HO-2 (؊/؊) mice, there was marked renal functional impairment as reflected by an increase in plasma creatinine, associated with acute tubular damage and microvascular pathology as compared with HO-2 (؉/؉). In these animals, HO activity was decreased with a concomitant increase in superoxide anion. Upregulation of HO-1 in HO-2 (؊/؊) mice by weekly administration of cobalt protoporphyrin prevented the increase in plasma creatinine levels and tubulointerstitial and microvascular pathology. Inhibition of HO activity by administration of tin mesoporphyrin accentuated superoxide production and increased creatinine levels in hyperglycemic HO-2 (؊/؊) mice. In conclusion, HO-2 deficiency enhanced STZ-induced renal dysfunction and morphologic injury and HO-1 upregulation in HO-2 (؊/؊) mouse rescue and prevented the morphologic damage. These observations indicate that HO activity is essential in preserving renal function and morphology in STZ-induced diabetic mice probably via mitigation of concomitant oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Goodman¹,

Chander²,

Rezzani³

et al. 2006

Journal of the American Society of Nephrology

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“…Renal function was evaluated 24 h after glycerol injection through the estimation of the glomerular filtration rate (creatinine clearance). This AKI model (Gly-AKI) is characterized by renal ischemia and myoglobin-derived heme-iron-mediated renal oxidative stress [10][11][12][13][14] leading to severe tubular injury (necrosis and apoptosis), renal and systemic inflammatory response, preglomerular vasoconstriction, and acute renal failure. [15][16][17] Based on the previous studies in rats subjected to renal ischemia/reperfusion injury, 18,19 we expected that silymarin would have antioxidant and protective effect in Gly-AKI rats.…”

Section: Introductionmentioning

confidence: 99%

Silymarin exacerbates p53-mediated tubular apoptosis in glycerol-induced acute kidney injury in rats

2010

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Background/aims: Silymarin is an herbal extract with antioxidant properties that can reduce oxidative stressmediated injuries in murine models of liver, heart, and kidney diseases. Silymarin can also increase p53-mediated cellular apoptosis in vitro. We tested the effect of silymarin administration before glycerol-induced acute kidney injury (Gly-AKI) in rats. Methods: Renal function, tubular injury, oxidative stress, leukocytes infiltration, and renal expression of apoptosis regulating proteins (p53, p-p53, Bax, Bcl-2, survivin, and cleaved caspase-3) were evaluated 6 or 24 h after glycerol. Results: Silymarin exacerbated the renal impairment and tubular apoptosis but had no effect on tubular necrosis or renal leukocytes infiltration. Renal lipid and DNA peroxidation was increased after glycerol and silymarin did not reduce oxidative stress. Proteins p53, p-p53, and proapoptotic Bax were upregulated in Gly-AKI rats treated with silymarin, whereas anti-apoptotic Bcl-2 was reduced in this group. Cleaved caspase-3 was overexpressed in Gly-AKI rats, particularly when treated with silymarin. Survivin was less expressed in Gly-AKI than in controls, but this deficit was not aggravated by silymarin. Conclusion: The persistence of oxidative stress, inflammatory reaction, and tubular necrosis, as well as exacerbation of p53-mediated tubular apoptosis, led to a more severe renal impairment in Gly-AKI rats treated with silymarin.

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“…9), ischemia-reperfusion (10,11), transplant ischemia (12), and proteinuria induced tubular damage (13). Preloading animals with iron (14) worsens the disease, and, conversely, chelating iron with deferoxamine (DFO) (8,(15)(16)(17)(18)(19) or bacterial siderophores (20) blunts the damage. Iron-catalyzed damage is thought to be one of the earliest events in kidney dysfunction and is likely to be important in other organs, including the heart (20) and the liver (21).…”

Section: Introductionmentioning

confidence: 99%

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

et al. 2005

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Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with ironbinding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules.In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 μg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngaldependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.

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Iron, heme oxygenase, and glutathione: Effects on myohemoglobinuric proximal tubular injury

Cited by 126 publications

References 20 publications

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Silymarin exacerbates p53-mediated tubular apoptosis in glycerol-induced acute kidney injury in rats

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

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