Ishizaka Nobukazu, Aizawa Toru, Yamazaki Ieharu, Usui Shin-ichi, Mori Ichiro, Kurokawa Kiyoshi, Tang Shiow-Shih, Ingelfinger Julie R, Ohno Minoru, Nagai Ryozo
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan.
Lab Invest. 2002 Jan;82(1):87-96. doi: 10.1038/labinvest.3780398.
Acute experimental iron loading causes iron to accumulate in the renal tissue. The accumulation of iron may play a role in enhancing oxidant-induced tubular injury by producing increased amounts of reactive oxygen species. From findings in cells from heme oxygenase-1 (HO-1)-deficient mice, HO-1 is postulated to prevent abnormal intracellular iron accumulation. Recently, it has been reported that HO-1 is induced in the renal tubular epithelial cells, in which iron is deposited after iron loading, and that this HO-1 induction may be involved in ameliorating iron-induced renal toxicity. We previously showed that chronic administration of angiotensin II to rats induces HO-1 expression in the tubular epithelial cells. These observations led us to investigate whether there is a link between iron deposition and HO-1 induction in renal tubular cells in rats undergoing angiotensin II infusion. In the present study, rats were given angiotensin II for continuously 7 days. Prussian blue staining revealed the distinct deposits of iron in the proximal tubular epithelial cells after angiotensin II administration. Electron microscopy demonstrated that iron particles were present in the lysosomes of these cells. Histologic and immunohistochemical analyses showed that stainable iron and immunoreactive ferritin and HO-1 were colocalized in the tubular epithelial cells. Treatment of angiotensin II-infused rats with an iron chelator, deferoxamine, blocked the abnormal iron deposition in kidneys and also the induced expression of HO-1 and ferritin expression. Furthermore, deferoxamine treatment suppressed the angiotensin II-induced increase in the urinary excretion of protein and N-acetyl-beta-D-glucosaminidase, a marker of tubular injury; however, deferoxamine did not affect the angiotensin II-induced decrease in glomerular filtration rate. These results suggest that angiotensin II causes renal injury, in part, by inducing the deposition of iron in the kidney.
急性实验性铁负荷会导致铁在肾组织中蓄积。铁的蓄积可能通过产生更多的活性氧，在增强氧化剂诱导的肾小管损伤中发挥作用。从血红素加氧酶-1（HO-1）缺陷小鼠的细胞研究结果推测，HO-1可防止细胞内铁异常蓄积。最近有报道称，铁负荷后铁沉积于肾小管上皮细胞中，且该细胞中HO-1被诱导表达，这种HO-1的诱导可能参与减轻铁诱导的肾毒性。我们之前发现，给大鼠长期输注血管紧张素II可诱导肾小管上皮细胞中HO-1表达。这些观察结果促使我们研究在接受血管紧张素II输注的大鼠肾小管细胞中，铁沉积与HO-1诱导之间是否存在联系。在本研究中，给大鼠连续7天输注血管紧张素II。普鲁士蓝染色显示，血管紧张素II给药后，近端肾小管上皮细胞中有明显的铁沉积。电子显微镜检查表明，这些细胞的溶酶体中存在铁颗粒。组织学和免疫组织化学分析显示，可染色铁、免疫反应性铁蛋白和HO-1在肾小管上皮细胞中共定位。用铁螯合剂去铁胺治疗血管紧张素II输注的大鼠，可阻止肾脏中异常的铁沉积，以及HO-1和铁蛋白表达的诱导。此外，去铁胺治疗可抑制血管紧张素II诱导的蛋白尿排泄增加以及肾小管损伤标志物N-乙酰-β-D-氨基葡萄糖苷酶的增加；然而，去铁胺并不影响血管紧张素II诱导的肾小球滤过率降低。这些结果表明，血管紧张素II部分通过诱导铁在肾脏中的沉积而导致肾损伤。
Zotero 插件