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

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

doi:10.1172/JCI23056

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

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

Research output: Contribution to journal › Article › peer-review

862 Scopus citations

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.

Original language	English (US)
Pages (from-to)	610-621
Number of pages	12
Journal	Journal of Clinical Investigation
Volume	115
Issue number	3
DOIs	https://doi.org/10.1172/JCI23056
State	Published - Mar 2005
Externally published	Yes

ASJC Scopus subject areas

General Medicine

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Mori, K., Lee, H. T., Rapoport, D., Drexler, I. R., Foster, K., Yang, J., Schmidt-Ott, K. M., Chen, X., Jau, Y. L., Weiss, S., Mishra, J., Cheema, F. H., Markowitz, G., Suganami, T., Sawai, K., Mukoyama, M., Kunis, C., D'Agati, V., Devarajan, P., & Barasch, J. (2005). Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. Journal of Clinical Investigation, 115(3), 610-621. https://doi.org/10.1172/JCI23056

Mori, K, Lee, HT, Rapoport, D, Drexler, IR, Foster, K, Yang, J, Schmidt-Ott, KM, Chen, X, Jau, YL, Weiss, S, Mishra, J, Cheema, FH, Markowitz, G, Suganami, T, Sawai, K, Mukoyama, M, Kunis, C, D'Agati, V, Devarajan, P & Barasch, J 2005, 'Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury', Journal of Clinical Investigation, vol. 115, no. 3, pp. 610-621. https://doi.org/10.1172/JCI23056

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title = "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.",

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

year = "2005",

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doi = "10.1172/JCI23056",

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AU - Mori, Kiyoshi

AU - Lee, H. Thomas

AU - Rapoport, Dana

AU - Drexler, Ian R.

AU - Foster, Kirk

AU - Yang, Jun

AU - Schmidt-Ott, Kai M.

AU - Chen, Xia

AU - Jau, Yi Li

AU - Weiss, Stacey

AU - Mishra, Jaya

AU - Cheema, Faisal H.

AU - Markowitz, Glenn

AU - Suganami, Takayoshi

AU - Sawai, Kazutomo

AU - Mukoyama, Masashi

AU - Kunis, Cheryl

AU - D'Agati, Vivette

AU - Devarajan, Prasad

AU - Barasch, Jonathan

PY - 2005/3

Y1 - 2005/3

N2 - 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.

AB - 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.

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

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