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      Iron Dextran Causes Renal Iron Deposition but Not Renal Dysfunction in Angiotensin II-Treated and Untreated Rats

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          Background: Angiotensin II infusion into rats causes iron deposition in the kidney, which may augment the pro-proteinuric effects of this octapeptide. We have investigated whether administration of iron mimics the renal damage induced by angiotensin II. Methods: Rats were treated with iron dextran at a total dose of 960 mg/kg either with or without angiotensin II treatment at a dose of 0.7 mg/kg/day for 7 days. Protein expression of ferritin and heme oxygenase-1, an oxidative stress-sensitive gene, was determined by Western blot analysis and immunohistochemistry. Results: Administration of iron dextran did not significantly increase proteinuria or decrease creatinine clearance in the rats with or without angiotensin II treatment. Prussian blue staining showed that iron deposition was observed mainly in the glomerular and medullar regions in the iron dextran-treated rats, but in the tubular epithelial cells in angiotensin II-infused rats. Administration of iron dextran upregulated ferritin, but not heme oxygenase-1. Conclusion: Iron dextran did not enhance or cause the renal dysfunction in the angiotensin II-treated or untreated rats, respectively. The distribution of deposited iron and presumably the type of iron compound administered may be important determinants of the development of renal injury.

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          Most cited references 13

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          Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.

          Heme proteins such as myoglobin or hemoglobin, when released into the extracellular space, can instigate tissue toxicity. Myoglobin is directly implicated in the pathogenesis of renal failure in rhabdomyolysis. In the glycerol model of this syndrome, we demonstrate that the kidney responds to such inordinate amounts of heme proteins by inducing the heme-degradative enzyme, heme oxygenase, as well as increasing the synthesis of ferritin, the major cellular repository for iron. Prior recruitment of this response with a single preinfusion of hemoglobin prevents kidney failure and drastically reduces mortality (from 100% to 14%). Conversely, ablating this response with a competitive inhibitor of heme oxygenase exacerbates kidney dysfunction. We provide the first in vivo evidence that induction of heme oxygenase coupled to ferritin synthesis is a rapid, protective antioxidant response. Our findings suggest a therapeutic strategy for populations at a high risk for rhabdomyolysis.
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            In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage.

            The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin II in the regulation of renal klotho gene expression. Long-term infusion of angiotensin II downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type 1 receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3x10(10) plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer. Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.
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              In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity.

              Cisplatin is a widely used antineoplastic agent that has nephrotoxicity as a major side effect. The underlying mechanism of this nephrotoxicity is still not well known. Iron has been implicated to play an important role in several models of tissue injury, presumably through the generation of hydroxyl radicals via the Haber-Weiss reaction or other highly toxic free radicals. In the present study we examined the catalytic iron content and the effect of iron chelators in an in vitro model of cisplatin-induced cytotoxicity in LLC-PK1 cells (renal tubular epithelial cells) and in an in vivo model of cisplatin-induced acute renal failure in rats. Exposure of LLC-PK1 cells to cisplatin resulted in a significant increase in bleomycin-detectable iron (iron capable of catalyzing free radical reactions) released into the medium. Concurrent incubation of LLC-PK1 cells with iron chelators including deferoxamine and 1,10-phenanthroline significantly attenuated cisplatin-induced cytotoxicity as measured by lactate dehydrogenase (LDH) release. Bleomycin-detectable iron content was also markedly increased in the kidney of rats treated with cisplatin. Similarly, administration of deferoxamine in rats provided marked functional (as measured by blood urea nitrogen and creatinine) and histological protection against cisplatin-induced acute renal failure. In a separate study, we examined the role of hydroxyl radical in cisplatin-induced nephrotoxicity. Incubation of LLC-PK1 cells with cisplatin caused an increase in hydroxyl radical formation. Hydroxyl radical scavengers, dimethyl sulfoxide, mannitol and benzoic acid, significantly reduced cisplatin-induced cytotoxicity and, treatment with dimethyl sulfoxide or dimethylthiourea provided significant protection against cisplatin-induced acute renal failure. Taken together, our data strongly support a critical role for iron in mediating tissue injury via hydroxyl radical (or a similar oxidant) in this model of nephrotoxicity.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                December 2004
                20 December 2004
                : 98
                : 4
                : p107-p113
                Departments of aCardiovascular Medicine and bNephrology, University of Tokyo Graduate School of Medicine, Tokyo, and cDepartment of Pathology, Wakayama Medical University, Wakayama, Japan
                81559 Nephron Physiol 2004;98:p107–p113
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 1, References: 24, Pages: 1
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                Original Paper

                Cardiovascular Medicine, Nephrology

                Ferritin, Proteinuria, Angiotensin II, Iron overload, Heme oxygenase-1


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