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Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

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Item Type:Article
Title:Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury
Creators Name:Mori, K. and Lee, H.T. and Rapoport, D. and Drexler, I.R. and Foster, K. and Yang, J. and Schmidt-Ott, K.M. and Chen, X. and Li, J.Y. and Weiss, S. and Mishra, J. and Cheema, F.H. and Markowitz, G. and Suganami, T. and Sawai, K. and Mukoyama, M. and Kunis, C. and D'Agati, V. and Devarajan, P. and Barasch, J.
Abstract: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.
Keywords:Acute-Phase Proteins, Creatinine, Endocytosis, Epithelial Cells, Heme Oxygenase (Decyclizing), Heme Oxygenase-1, Iron, Kidney, Kidney Cortex Necrosis, Kidney Tubules, Lipocalins, Macromolecular Substances, Membrane Proteins, Inbred C57BL Mice, Oncogene Proteins, Proto-Oncogene Proteins, Reperfusion Injury, Reperfusion Injury, Animals, Mice
Source:Journal of Clinical Investigation
ISSN:0021-9738
Publisher:American Society for Clinical Investigation (U.S.A.)
Volume:115
Number:3
Page Range:610-621
Date:March 2005
Official Publication:https://doi.org/10.1172/JCI23056
PubMed:View item in PubMed

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