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

TLDR

Neutrophil gelatinase–associated lipocalin (Ngal) forms a complex with iron‑binding siderophores that can convert renal progenitors into epithelial tubules, suggesting an endogenous protective role in kidney injury. The study tests whether the Ngal:siderophore:Fe complex protects adult kidney epithelial cells or speeds their recovery after injury. Protection requires endocytic delivery of Ngal, its siderophore, and iron to proximal tubule cells, as blocking the siderophore with gallium abolishes the rescue. In a mouse ischemia‑reperfusion model, a single early dose of Ngal:siderophore:Fe dramatically protected kidneys, reduced azotemia, upregulated heme‑oxygenase‑1, preserved N‑cadherin, inhibited cell death, and similar accumulation was observed in human kidney injury, revealing a novel iron‑traffic pathway that offers a new therapeutic approach.

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.