Endocytic Delivery of Lipocalin-siderophore-iron Complex Rescues the Kidney from Ischemia-reperfusion Injury

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2005 Feb 16

PMID 15711640

Citations 390

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 DAgati

Prasad Devarajan

Jonathan Barasch

Affiliations

Soon will be listed here.

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.

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