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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Rescue of mouse ATN by Ngal. (A) Holo-Ngal (100 μg) was injected into th...
Rescue of mouse ATN by Ngal. (A) Holo-Ngal (100 μg) was injected into the peritoneum 15 minutes before renal pedicle cross-clamp and 30 minutes of ischemia. Kidneys were harvested after 24 hours of reperfusion for H&E staining. The ischemic kidneys (ATN) demonstrated loss of tubular nuclei (ATN, bottom) as well as the presence of cortical and medullary intratubular casts (ATN, middle). In contrast, Ngal pretreatment resulted in preservation of cortical tubules (ATN+Ngal, bottom) and reduced cortical-medullary casts (ATN+Ngal, middle). (B) PAS staining highlighted the luminal casts in the ischemic kidney (ATN) as well as the rescue of cortical tubules by pretreatment with Ngal (ATN+Ngal). (C) Area of proximal convoluted tubular necrosis was evaluated by the Jablonski scale, which demonstrated rescue of the ischemic cortex by Ngal (0: no necrosis; 1: isolated necrotic cells; 2: focal necrosis in inner cortex; 3: diffuse necrosis in inner cortex; 4: necrosis involving whole cortex). *P < 0.05, **P < 0.01 vs. untreated ischemic kidneys. Scale bars: A, top row, 800 μm; middle row, 24 μm; bottom row, 11 μm; B, top row, 800 μm; bottom row, 24 μm.