Protective Role of Hepcidin in Polymicrobial Sepsis and Acute Kidney Injury

Abstract

Background: Acute kidney injury (AKI) portends worse prognosis following sepsis, with limited available interventions. Host iron acquisition by pathogens and systemic inflammatory response are key events in the pathogenesis of sepsis. In sepsis, hepcidin induces iron sequestration to limit iron availability to pathogens. Hepcidin is also known to limit inflammation. Since its role in pathophysiology of sepsis-associated AKI is unknown, we investigated the effect of exogenous hepcidin in endotoxin- and peritonitis-induced pathology and AKI. Methods: C57BL/6 mice were treated with saline or 50–100 µg of hepcidin, pre- and post-LPS injection, or cecal ligation and puncture (CLP, model of peritonitis). Splenectomized mice were challenged with LPS, with and without hepcidin. Mice were euthanized at 24 h after LPS injection and at different time points after CLP. Systemic inflammation and renal injury markers were assessed. Direct effect of hepcidin on renal tubular and endothelial cells was evaluated using endotoxin-induced cytotoxic serum. Role of heavy chain ferritin (H-ferritin) in mediating hepcidin-induced anti-inflammatory effect on LPS stimulated macrophages was evaluated with siRNA studies. Results: Twenty-four hours pretreatment with hepcidin significantly reduced LPS-induced AKI. Hepcidin ameliorated LPS-induced increase in serum TNFα and renal Cox-2, and prevented loss in PGC1α and cytochrome c oxidase activity. This was associated with reduced glomerular injury and preserved mitochondrial structure. Hepcidin did not exert direct protection on the renal parenchymal cells but reduced endotoxin-induced serum cytotoxicity to mitigate renal injury. Splenectomy reduced LPS-induced early inflammation and AKI, independent of hepcidin, indicating the importance of systemic inflammation. Higher splenic H-ferritin in hepcidin-treated animals was associated with reduced splenocytes apoptosis and inflammation. Hepcidin reduced LPS-induced IL-6 secretion in macrophages in H-ferritin dependent manner. Hepcidin significantly reduced CLP-induced AKI, and mortality (20% hepcidin treated vs 80% PBS treated). Importantly hepcidin reduced bacteremia and AKI even when administered after onset of sepsis. Conclusion: We demonstrate a protective role of hepcidin in endotoxin- and peritonitis-induced pathologies and AKI, exerted primarily through its anti-inflammatory effects, and antibacterial property. Macrophage H-ferritin plays an important role in hepcidin-mediated protection against endotoxin-induced inflammation. We uncover a novel prophylactic and therapeutic role of hepcidin in sepsis-associated bacteremia, AKI, and mortality.

Iron Homeostasis and Ferritin in Sepsis-Associated Kidney Injury

“…Interestingly, pretreatment of mice with hepcidin also protects against SA-AKI and mortality. Hepcidin mediated macrophage iron retention and consequently increased FtH expression [8].…”

“…Interestingly, pretreatment of mice with hepcidin also protects against SA-AKI and mortality. Hepcidin mediated macrophage iron retention and consequently increased FtH expression [8]. Several studies have demonstrated that iron chelation prior to induction of AKI is protective (Table 1); however, the effect of iron chelators following established renal injury is not well studied.…”

Resolvin D1 protects against sepsis‐induced cardiac injury in mice

“…Multiple organ dysfunction and circulatory failure in sepsis are caused by systemic inflammation after exposure to LPS 39,40 . As the largest immune organ, the spleen plays an important role during LPS‐induced systemic inflammation 41 .…”

Elevated serum iron level is a predictor of prognosis in ICU patients with acute kidney injury

“…It reduces extracellular iron levels through downregulating iron absorption in duodenal and ferroportin expression and cellular iron release in macrophages [18,20]. And the protective role of hepcidin in AKI provides evidence on the key role of iron in mediating AKI [21]. Meanwhile, a study involving 807 patients showed that plasm catalytic iron and hepcidin possibly be useful prognostic indicators in AKI patients [9].…”