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

• Published in: The Journal of clinical investigation 2005-03, Vol.115 (3), p.610-621
• Main Authors: Mori, Kiyoshi, Lee, H Thomas, Rapoport, Dana, Drexler, Ian R, Foster, Kirk, Yang, Jun, Schmidt-Ott, Kai M, Chen, Xia, Li, Jau Yi, Weiss, Stacey, Mishra, Jaya, Cheema, Faisal H, Markowitz, Glenn, Suganami, Takayoshi, Sawai, Kazutomo, Mukoyama, Masashi, Kunis, Cheryl, D'Agati, Vivette, Devarajan, Prasad, Barasch, Jonathan
• Format: Article
• Language: English
• Subjects: Acute-Phase Proteins - genetics; Acute-Phase Proteins - therapeutic use; Acute-Phase Proteins - urine; Animals; Bacterial infections; Biomedical research; Creatinine; Creatinine - blood; Disease; Endocytosis; Epithelial Cells - metabolism; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1; Humans; Hypoxia; Iron; Iron - metabolism; Ischemia; Kidney - cytology; Kidney - metabolism; Kidney - pathology; Kidney Cortex Necrosis - drug therapy; Kidney Cortex Necrosis - metabolism; Kidney Cortex Necrosis - pathology; Kidney Tubules - cytology; Kidney Tubules - metabolism; Kidney Tubules - pathology; Kidneys; Lipocalin-2; Lipocalins; Macromolecular Substances; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Molecular weight; Necrosis; Neutrophils; Oncogene Proteins - genetics; Oncogene Proteins - therapeutic use; Oncogene Proteins - urine; Proteins; Proto-Oncogene Proteins; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Siderophores - metabolism; Urine
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci23056

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.