Objective-We have investigated whether long-term administration of angiotensin (Ang) II causes ferritin induction and iron accumulation in the rat aorta, and their possible relation to regulatory effects on gene expression and vascular function in Ang II-infused animals. Methods and Results-Sprague-Dawley rats were given Ang II for 7 days via subcutaneously implanted osmotic minipumps. Ang II infusion caused a Ͼ20-fold increase in ferritin protein expression over control values. Immunohistochemistry showed that Ang II infusion markedly increased the ferritin expression in the aortic endothelial and adventitial cells, with some of the latter being identified as monocytes/macrophages. Prussian blue staining showed that stainable iron was observed in the adventitial layer of aorta from Ang II-infused animals, but not in the endothelial layer. Chelation of iron suppressed aortic induction of ferritin and also the oxidative stress markers, heme oxygenase-1 and 4-hydroxynonenal-modified protein adducts. In addition, iron chelation attenuated Ang II-induced impairment of aortic relaxations in response to acetylcholine and sodium nitroprusside and suppressed upregulation of mRNA levels of monocyte chemoattractant protein-1. Iron chelation also partially attenuated the medial thickening and perivascular fibrosis induced by Ang II infusion for 4 weeks. Conclusion-Ang

Abstract-Abnormal lipid metabolism may play a role in progressive renal failure. We studied whether lipid accumulation occurs and whether lipid deposits are colocalized with transforming growth factor-␤1 (TGF-␤1) in the kidney of angiotensin II-infused animals. Oil red O staining showed marked lipid deposition in the tubular epithelial and vascular wall cells of angiotensin II-treated but not in norepinephrine-treated rats. Histological analyses showed that increased amounts of superoxide and intense TGF-␤1 mRNA expression were present in lipid-positive tubular epithelial cells in angiotensin II-infused animals. Protein expression of sterol regulatory element-binding protein 1 (SREBP-1) and mRNA expression of fatty acid synthase in the kidney were Ϸ3 times and 1.5 times, respectively, higher in angiotensin II-treated rats than in controls. Treatment of angiotensin II-infused animals with an iron chelator, deferoxamine, attenuated the angiotensin II-induced increases in renal expression of SREBP-1 and fatty acid synthase and normalized the lipid content in the renal cortical tissues. Abnormal lipid metabolism may be associated with upregulation of TGF-␤1 expression and aberrant iron homeostasis in the kidneys of angiotensin II-infused animals. Key Words: angiotensin II Ⅲ transforming growth factors Ⅲ lipids P revious studies showed that accumulation of lipids in nonadipose tissues occurs in certain diseased conditions, and that it plays a crucial role in the pathogenesis of tissue damage, 1 a phenomenon referred to as lipotoxicity. 2 For example, lipid deposition in the arterial wall 3,4 is postulated to represent an early event in the development of atherosclerosis. 5 The accumulation of triglycerides (TGs) in cardiomyocytes 6,7 may be associated with contractile dysfunction, and excess TGs in the liver may promote hepatic fibrosis. 8 Lipid accumulation in the kidney may represent features of glomerular and tubulointerstitial damage. 9 We found that long-term administration of angiotensin II (Ang II) to rats caused marked deposition of iron 10 and upregulation of the expression of transforming growth factor-␤1 (TGF-␤1) in renal tubular epithelial cells. 11 We also found that iron chelation attenuated the Ang II-induced upregulation of TGF-␤1 in the kidney, suggesting a possible link between aberrant iron homeostasis and TGF-␤1 upregulation. However, unexpectedly, histological analysis showed that upregulation of TGF-␤1 mRNA and deposition of iron occurred in different tubular cells in most cases. The aims of the present study were to investigate whether accumulation of lipids occurs in the kidney of Ang II-infused animals and to investigate the relationship between lipid accumulation and TGF-␤1 in terms of localization. We also investigated whether Ang II infusion alter the expression of genes that have relation to the lipid metabolism, such as ATP-binding cassette transporter subfamily A-1 (ABCA1), scavenger receptor class B type 1 (SR-B1), sterol regulatory elementbinding protein 1 (SREBP-1), SREBP-2, 3-hydrox...

Due to recent discoveries of novel genes involved in iron metabolism, our understanding of the molecular mechanisms underlying iron metabolism has dramatically increased. We have previously shown that the administration of angiotensin II alters iron homeostasis in the rat kidney, which may in turn aggravate angio-