Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.
Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.
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DOI：
10.1172/jci23056
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发表时间：
2005-03
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通讯作者：
K. Mori;H. Lee;Dana Rapoport;Ian R. Drexler;Kirk Foster;Jun Yang;K. Schmidt-Ott;Xia Chen;Jau-yi Li;Stacey Weiss;J. Mishra;F. Cheema;G. Markowitz;T. Suganami;K. Sawai;M. Mukoyama;C. Kunis;V. D’Agati;P. Devarajan;J. Barasch
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作者：
K. Mori;H. Lee;Dana Rapoport;Ian R. Drexler;Kirk Foster;Jun Yang;K. Schmidt-Ott;Xia Chen;Jau-yi Li;Stacey Weiss;J. Mishra;F. Cheema;G. Markowitz;T. Suganami;K. Sawai;M. Mukoyama;C. Kunis;V. D’Agati;P. Devarajan;J. Barasch
中性粒细胞明胶酶相关脂蛋白(NGAL)，也称为铁黄素，与铁结合铁载体(NGAL：铁载体：Fe)形成复合体。这种复合体将肾祖细胞转化为上皮管。在这项研究中，我们验证了NGAL：铁载体：铁保护成人肾上皮细胞或加速其损伤恢复的假设。使用严重肾功能衰竭、缺血-再灌注损伤的小鼠模型，我们表明，在疾病的初始阶段引入单剂量NGAL(10微克)，显著保护肾脏并减轻氮质血症。NGAL的活性依赖于蛋白质及其铁载体向近端小管的输送。铁也必须输送，因为用镓封锁铁载体会阻止对缺血的救援。NGAL：铁载体：铁复合体上调血红素加氧酶-1，一种保护酶，保留近端小管N-钙粘附素，并抑制细胞死亡。由于小鼠尿中含有一种依赖于NGAL的类铁载体活性，内源性NGAL也可能起到保护作用。事实上，NGAL在人肾皮质小管以及肾毒性和缺血损伤后的血液和尿液中高度积聚。我们揭示了一种我们认为在人类和小鼠肾脏疾病中被激活的铁交通的新途径，并为他们的治疗提供了一种独特的方法。
Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with iron-binding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules. In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 microg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngal-dependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.