title: Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis.
abstract: Iron-mediated oxidative stress is implicated in the pathogenesis of renal ischemia-reperfusion injury. Hepcidin is an endogenous acute phase hepatic hormone that prevents iron export from cells by inducing degradation of the only known iron export protein, ferroportin. In this study, we used a mouse model to investigate the effect of renal ischemia-reperfusion injury on systemic iron homeostasis and determine if dynamic modulation of iron homeostasis with hepcidin has therapeutic benefit in the treatment of AKI. Renal ischemia-reperfusion injury induced hepatosplenic iron export through increased ferroportin expression, which resulted in hepatosplenic iron depletion and an increase in serum and kidney nonheme iron levels. Exogenous hepcidin treatment prevented renal ischemia-reperfusion-induced changes in iron homeostasis. Hepcidin also decreased kidney ferroportin expression and increased the expression of cytoprotective H-ferritin. Hepcidin-induced restoration of iron homeostasis was accompanied by a significant reduction in ischemia-reperfusion-induced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration. Hepcidin -: deficient mice demonstrated increased susceptibility to ischemia-reperfusion injury compared with wild-type mice. Reconstituting hepcidin-deficient mice with exogenous hepcidin induced hepatic iron sequestration, attenuated the reduction in renal H-ferritin and reduced renal oxidative stress, apoptosis, inflammation, and tubular injury. Hepcidin-mediated protection was associated with reduced serum IL-6 levels. In summary, renal ischemia-reperfusion injury results in profound alterations in systemic iron homeostasis. Hepcidin treatment restores iron homeostasis and reduces inflammation to mediate protection in renal ischemia-reperfusion injury, suggesting that hepcidin-ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI.
authors: Division of Nephrology, Center for Inflammation, Immunity and Regenerative Medicine, and.
authors: Yogesh
authors: Y
authors: Scindia
authors: Division of Nephrology, Center for Inflammation, Immunity and Regenerative Medicine, and.
authors: Paromita
authors: P
authors: Dey
authors: Division of Nephrology.
authors: Abhinav
authors: A
authors: Thirunagari
authors: Division of Nephrology, Center for Inflammation, Immunity and Regenerative Medicine, and.
authors: Huang
authors: H
authors: Liping
authors: Center for Inflammation, Immunity and Regenerative Medicine, and Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia.
authors: Diane L
authors: DL
authors: Rosin
authors: Division of Nephrology.
authors: Matteo
authors: M
authors: Floris
authors: Division of Nephrology, Center for Inflammation, Immunity and Regenerative Medicine, and.
authors: Mark D
authors: MD
authors: Okusa
authors: Division of Nephrology, Center for Inflammation, Immunity and Regenerative Medicine, and swami@virginia.edu.
authors: Sundararaman
authors: S
authors: Swaminathan
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D005786:Gene Expression Regulation; D064451:Hepcidins / Q000097:blood / Q000737:chemistry*; D006706:Homeostasis; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D007501:Iron / Q000097:blood / Q000737:chemistry*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress; D015427:Reperfusion Injury / Q000473:pathology*; D013154:Spleen / Q000166:cytology / Q000473:pathology
chemical_list: D064451:Hepcidins; D015850:Interleukin-6; C577686:interleukin-6, mouse; D007501:Iron; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse
keywords: acute kidney injury; acute renal failure; hepcidin; iron homeostasis; ischemia-reperfusion; oxidative stress