Role of the abnormal iron metabolism in the development of angiotensin II-induced renal damage

铁代谢异常在血管紧张素II诱导的肾损伤发生过程中的作用

• 批准号: 13671098
• 负责人: ISHIZAKA Nobukazu
• 金额: $ 2.24万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671098/
• 关键词: Angiotensin II; Proteinuria; Renal function; Cardiovascular damage; Oxdative stress; Iron metabol ism; Iron overload; Chelator; 腎機能障害; 高血圧; 筋障害; 老化遺伝子

We have reported that continuous administration of angiotensin II caused induction of heme oxygenase-1 (HO-1) in the renal tubular epithelial cells in rats. Recent studies have demonstrated that HO-1 plays a crucial role in maintaining the intracellular iron homeostasis, as well as in heme metabolism. We investigated whether abnormal iron metabolism could be seen in the kidney of rats given chronic angiotensin II. Prussian blue staining showed histologic iron deposition in the tubular epithelial cells where strong HO-1 expression could also be demonstrated after 7-day administration of angiotensin II. Treatment of these rats with iron chelator, deferoxamine, suppressed not only renal iron deposition, but also angiotensin II-induced increase in urinary protein excretion. We generated iron overload rat model to examine iron overload could mimic the effects of angiotensin II on renal function. However, iron overload, achieved by the administration of iron-dextran did not enhance urinary prote in excretion. This was possibly because, unlike angiotensin II-infusion model, iron-dextran treatment caused iron deposition in the mesangial and interstitial cells, but not tubular epithelial cells. Conversely, it is possible, renal tubular iron deposition may play a crucial role in the development of proteinuria.In other set of experiments, we showed that continuous administration of angiotensin II caused aging-related gene, klotho, in the kidney, suggesting the link between renin-angiotensin system and aging process. We also showed some evidence that abnormal iron metabolism may also involved in one of the mechanisms of angiotensin II-induced cardiovascular damage in our animal model.

我们已报道持续给予血管紧张素II可诱导大鼠肾小管上皮细胞中血红素加氧酶-1(HO-1)的表达。最近的研究表明，HO-1在维持细胞内铁稳态以及在血红素代谢中起着至关重要的作用。我们研究了慢性血管紧张素II诱导的大鼠肾脏铁代谢是否异常。普鲁士蓝染色显示肾小管上皮细胞铁沉积，血管紧张素II给药7天后，肾小管上皮细胞也可见HO-1的强表达。用铁络合剂去铁胺治疗这些大鼠，不仅能抑制肾组织铁沉积，还能抑制血管紧张素II诱导的尿蛋白排泄增加。我们建立了铁超载大鼠模型，以检验铁超载是否能模拟血管紧张素II对肾功能的影响。然而，通过给予右旋糖酸铁实现的铁负荷并没有增加尿液中的蛋白排泄。这可能是因为，与血管紧张素II输注模型不同，铁-葡聚糖治疗引起了系膜和间质细胞中的铁沉积，但不是肾小管上皮细胞中的铁沉积。相反，肾小管铁沉积可能在蛋白尿的发育中起关键作用。在其他一组实验中，我们发现持续给予血管紧张素II会导致肾脏中与衰老相关的基因klotho，这表明肾素-血管紧张素系统与衰老过程之间存在联系。我们还提供了一些证据，表明铁代谢异常也可能参与了血管紧张素II诱导的动物模型心血管损伤的机制之一。

项目成果

Ishizaka Y, Ishizaka N, Takahashi E, Unuma T, Tooda E, Hashimoto H, Nagai R, Yamakado M.: "Association between hepatitis Cvirus core protein and carotid atherosclerosis"Girc J. 67(1). 26-30 (2003)

Ishizaka Y、Ishizaka N、Takahashi E、Unuma T、Tooda E、Hashimoto H、Nagai R、Yamakado M.：“丙型肝炎病毒核心蛋白与颈动脉粥样硬化之间的关联”Girc J. 67(1)。

Sata M, et al.: "Mouse genetic evidence that tranilast reduces smooth muscle cell hyperplasia via a p21(WAF1)-dependent pathway"Arterioscler Thromb Vasc Biol. 22・8. 1305-1309 (2002)

Sata M 等人：“曲尼司特通过 p21(WAF1) 依赖性途径减少平滑肌细胞增生的小鼠遗传学证据”Arterioscler Thromb Vasc Biol. 1305-1309 (2002)。

Ishizaka N, Aizawa T, Ohno M, Usui S, Mori I, Tang S-S, Ingelfinger JR, Kimura S, and Nagai R: "Regulation and localization of HSP70 and HSP25 in the kidney of rats undergoing chronic administration of Angiotensin II"Hypertension. 39. 122-128 (2002)

Ishizaka N、Aizawa T、Ohno M、Usui S、Mori I、Tang S-S、Ingelfinger JR、Kimura S 和 Nagai R：“慢性服用血管紧张素 II 的大鼠肾脏中 HSP70 和 HSP25 的调节和定位”高血压。

Ishizaka N, Saito K, Mitani H, Yamazaki I, Sata M, Usui S, Mori I, Ohno M, Nagai R.: "Iron overload augments angiotensin II-induced cardiac fibrosis and promotes neointima formation"Circulation. 106(14). 1840-1846 (2002)

Ishizaka N、Saito K、Mitani H、Yamazaki I、Sata M、Usui S、Mori I、Ohno M、Nagai R.：“铁超负荷会增强血管紧张素 II 诱导的心脏纤维化并促进新内膜形成”循环。