Abnormal Iron Deposition in Renal Cells in the Rat with Chronic Angiotensin II Administration

Ishizaka, Nobukazu; Aizawa, Toru; Yamazaki, Ieharu; Usui, Shin-ichi; Mori, Ichiro; Kurokawa, Kiyoshi; Tang, Shiow‐Shih; Ingelfinger, Julie R.; Ohno, Minoru; Nagai, Ryozo

doi:10.1038/labinvest.3780398

Cited by 33 publications

(53 citation statements)

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“…Thus, iron may act to promote arteriosclerosis and neointimal formation when other proatherogenic stimuli, such as endothelium removal or increased circulatory levels of angiotensin II, are present. We previously reported the high expression of HO-1 in the renal cells containing iron deposits after angiotensin II infusion, 6 which suggested that HO-1 induction might be a possible marker of intracellular iron deposition. However, confocal microscopic analysis revealed that unlike in the kidney, HO-1 expression does not appear to be a good marker for iron deposition in cardiac cells under our experimental conditions.…”

Section: Ishizaka Et Almentioning

confidence: 99%

“…Immunohistochemistry was performed as described previously. 6 Primary antibodies against rat macrophage/monocyte (ED-1; Chemicon International), rat HO-1 (StressGen), human ␣-SM actin (Sigma) and rat ferritin were used at 1/200, 1/200, 1/1000, and 1/200 dilutions, respectively. For immunofluorescence staining, rhodamine-conjugated anti-mouse (Chemicon International) and fluorescein-conjugated anti-rabbit (Sigma) antibodies were used at a 1/100 dilution.…”

Section: Histological and Immunohistochemical Analysesmentioning

confidence: 99%

“…Polyclonal antibody against rat ferritin (Panapharm) was used at a 1/2000 dilution. 6 The ECL Western blotting system (Amersham) was used for detection. Bands were visualized with the use of a lumino-analyzer (Fuji Photo Film).…”

Section: Protein Purification and Western Blot Analysismentioning

confidence: 99%

“…7 Recent studies have demonstrated that HO-1 also plays a crucial role in controlling the intracellular iron content and thus the extent of oxidant-induced cellular injury. 8 -10 Data from our laboratory 6 and others 11 have shown that HO-1 is induced in renal cells with abnormal iron accumulation. 12 In the present study, we investigated the effect of iron chelation and iron overload on angiotensin II-induced cardiac damage in rats.…”

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confidence: 99%

“…4,5 We have previously reported that long-term administration of angiotensin II results in an abnormal iron deposition in the lysosome of renal tubular epithelial cells, which may mediate proproteinuric effects of angiotensin II. 6 Heme oxygenase-1 (HO-1) is an inducible form of heme oxygenase that is a rate-limiting enzyme of heme degradation. 7 Recent studies have demonstrated that HO-1 also plays a crucial role in controlling the intracellular iron content and thus the extent of oxidant-induced cellular injury.…”

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confidence: 99%

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Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation

et al. 2002

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Background-Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II-induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. Methods and Results-Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted in an augmentation of cardiac fibrosis and the generation of neointimal cells in the coronary artery in angiotensin II-infused rats. By contrast, neointima was not formed in the cardiac vessels in norepinephrine-infused rats with iron overload. Conclusions-Cardiac iron deposition may be involved in the development of cardiac fibrosis induced by angiotensin II.In addition, iron overload may enhance the formation of neointima under conditions of increased circulating angiotensin II but not catecholamines.

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Section: Ishizaka Et Almentioning

confidence: 99%

Section: Histological and Immunohistochemical Analysesmentioning

confidence: 99%

Section: Protein Purification and Western Blot Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation

et al. 2002

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Systemic and local hepcidin as emerging and important peptides in renal homeostasis and pathology

Vela

2018

BioFactors

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Recent data suggest that the importance of hepcidin goes beyond its classical role in controlling systemic iron metabolism. Local hepcidins are emerging as important peptides for organ homeostasis in the brain, heart, blood vessels, and in cancer as well. Similarly, accumulating data indicate that hepcidin does seem to be an important factor in renal homeostasis. This review encompasses present knowledge concerning the role of hepcidin in renoprotection and its use as a biomarker of kidney diseases. Understanding the role of hepcidin in kidneys is important due to its relevance for kidney physiology and its potential therapeutic application in kidney pathologies. © 2018 BioFactors, 45(2):118–134, 2019

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Iron homeostasis, recycling and vulnerability in the stressed kidney: A neglected dimension of iron‐deficient heart failure

Packer

2024

European J of Heart Fail

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The available evidence suggests that the kidney may contribute importantly to the development of an iron deficiency state in patients with heart failure and may be injured by therapeutic efforts to achieve iron repletion. The exceptional workload of the proximal renal tubule requires substantial quantities of iron for ATP synthesis, which it derives from Fe3+ bound to transferrin in the bloodstream. Following ferrireduction, Fe2+ is conveyed by divalent transporters (e.g. DMT1) out of the endosome of the proximal renal tubule, and highly reactive Fe2+ can be directed to the mitochondria, sequestered safely in a ferritin nanocage or exported through the actions of hepcidin‐inhibitable ferroportin. The actions of ferroportin, together with transferrin endocytosis and DMT1‐mediated transport, play a key role in the recycling of iron from the tubular fluid into the bloodstream and preventing the loss of filtered iron in the urine. Activation of endogenous neurohormonal systems and proinflammatory signalling in heart failure decrease megalin‐mediated uptake and DMT1 expression, and increase hepcidin‐mediated suppression of ferroportin, promoting the loss of iron in the urine and contributing to the development of an iron deficiency state. Furthermore, the failure of ferroportin‐mediated efflux at the basolateral membrane heightens the susceptibility of the renal tubules to cytosolic excesses of Fe2+, causing lipid peroxidation and synchronized cell death (ferroptosis) through the iron‐dependent free radical theft of electrons from lipids in the cell membrane. Ferroptosis is a central mechanism to most disorders that can cause acute and chronic kidney disease. Short‐term bolus administration of intravenous iron can cause oxidative stress and is accompanied by markers of renal injury. Experimentally, long‐term maintenance of an iron‐replete state is accompanied by accelerated loss of nephrons, oxidative stress, inflammation and fibrosis. Intravenous iron therapy increases glomerular filtration rate rapidly in patients with heart failure (perhaps because of a haemodynamic effect) but not in patients with chronic kidney disease, and the effects of intravenous iron on the progression of renal dysfunction in the long‐term trials — AFFIRM‐AHF, IRONMAN and HEART‐FID — have not yet been reported. Given the potential role of dysregulated renal iron homeostasis in the pathogenesis of iron deficiency and the known vulnerability of the kidney to intravenous iron, the appropriate level of iron repletion with respect to the risk of acute and chronic kidney injury in patients with heart failure requires further study.

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Abnormal Iron Deposition in Renal Cells in the Rat with Chronic Angiotensin II Administration

Cited by 33 publications

References 30 publications

Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation

Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation

Systemic and local hepcidin as emerging and important peptides in renal homeostasis and pathology

Iron homeostasis, recycling and vulnerability in the stressed kidney: A neglected dimension of iron‐deficient heart failure

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