Hepcidin Exacerbates Iron Metabolism Imbalance in Septic Mice

Abstract

Liyan Wu,1 Zhenyan Yuan,1 Min Wang,1 Xiaomeng Fu,1 Xiaohui Liu,1 Bing Wei,2 Yugeng Liu1 1Department of Infectious Diseases and Clinical Microbiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100043, People’s Republic of China; 2Emergency Medicine Clinical Research Center, Beijing Chaoyang Hospital, Capital Medical University, & Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Clinical Center for Medicine in Acute Infection, Capital Medical University, Beijing, 100043, People’s Republic of ChinaCorrespondence: Bing Wei; Yugeng Liu, Email [email protected]; [email protected]: Sepsis is a life-threatening condition associated with acute organ dysfunction. Iron is an essential trace element for multicellular organisms and almost all microorganisms, and its role in sepsis has been increasingly recognized. The aim of this study was to investigate the changes in iron metabolism in caecal ligation and puncture solution (CLP) -induced septic mice and the effects of hepcidin pretreatment on serum inflammatory marker levels and liver iron metabolism in CLP-induced septic mice.Methods: C57BL/6 mice were given normal saline, CLP (peritonitis model) or 100 μg of hepcidin via intraperitoneal injection. The experimental animals were divided into 4 groups: the control group, model group (CLP), hepcidin pretreatment Groups CLP+hepcidin-2h and CLP+hepcidin-24 h. Blood samples were collected at 6, 12 and 24 hours after CLP surgery, and the mice were euthanized and livers were obtained.Results: ELISA revealed that hepcidin pretreatment, especially 2 hours in advance (p< 0.01), increased the serum hepcidin, TNF-a and IL-6 in CLP-induced septic mice; the serum iron content of CLP-related septic mice decreased (P< 0.01), while the liver iron content increased (P< 0.01); Hepcidin pretreatment reduced the serum iron (P< 0.05) at 6 h and 12 h and liver iron concentrations (P< 0.01) at 6 h, 12 h and 24 h in CLP-related septic mice. Western blotting revealed that the hepatic iron absorption-related proteins transferrin receptor-2 (TFR2), ZRT/IRT-like protein 14 (ZIP14) and divalent meta lion transporter-1 (DMT1) were elevated (P< 0.01); The iron-exporting protein ferroportin (SLC40A1) was decreased (P< 0.01) throughout CLP and CLP+hepcidin sepsis. Compared with CLP group, the protein expressions in the CLP+ hepcidin-2 h group were more obvious than that in the CLP+ hepcidin-24 h group.Conclusion: Hepcidin has proinflammatory effect. Hepcidin exacerbates iron metabolism imbalances in sepsis by influencing the expression of iron absorption-related proteins and iron export-related proteins.Keywords: hepcidin, sepsis, iron metabolism, SLC40A1, liver

Keywords

• hepcidin
• sepsis
• iron metabolism
• slc40a1
• liver