Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury
Kiyoshi Mori, … , Prasad Devarajan, Jonathan Barasch
Kiyoshi Mori, … , Prasad Devarajan, Jonathan Barasch
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):610-621. https://doi.org/10.1172/JCI23056.
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Article Nephrology

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

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 μg), 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.

Authors

Kiyoshi Mori, H. Thomas Lee, Dana Rapoport, Ian R. Drexler, Kirk Foster, Jun Yang, Kai M. Schmidt-Ott, Xia Chen, Jau Yi Li, Stacey Weiss, Jaya Mishra, Faisal H. Cheema, Glenn Markowitz, Takayoshi Suganami, Kazutomo Sawai, Masashi Mukoyama, Cheryl Kunis, Vivette D’Agati, Prasad Devarajan, Jonathan Barasch

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Figure 1

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Ngal expression in ATN of human (A–D) and mouse (E). (A) Monoclonal anti...
Ngal expression in ATN of human (A–D) and mouse (E). (A) Monoclonal anti–human Ngal (Mo) and polyclonal anti–mouse Ngal (Po) antibodies recognized recombinant (21-kDa) and native (25-kDa) human and mouse Ngal. Occasionally, higher–molecular weight species (approximately 35 kDa and 66 kDa) were present in recombinant and native preparations; these might represent dimers and trimers of Ngal. A standard curve was constructed with 25, 5, 1, and 0.2 ng recombinant proteins on nonreducing gels. Human urine samples (0.1–20 μl) from patients with ATN showed high levels of Ngal, whereas samples from patients with chronic renal failure (CRF), patients with liver cirrhosis, hemochromatosis, or pancreatic carcinoma but lacking a renal diagnosis (Others), or normal subjects (Normal) had low levels of Ngal. (B) Similar data were obtained from human serum. (C and D) Geometric means (bar ± SD) of urinary (C) and serum (D) Ngal were compared in normal, CRF, and ATN groups. ATN was further divided into sepsis and nonsepsis. *P < 0.05, **P < 0.01, ***P < 0.001 vs. normal. (E) Mouse ATN was also associated with elevated urinary Ngal. The renal pedicle was cross-clamped for 30 minutes, and urine was collected at 24 hours of reperfusion and analyzed by immunoblot (5 μl/lane).