title: Hemojuvelin modulates iron stress during acute kidney injury: improved by furin inhibitor.
abstract: OBJECTIVE
  Free iron plays an important role in the pathogenesis of acute kidney injury (AKI) via the formation of hydroxyl radicals. Systemic iron homeostasis is controlled by the hemojuvelin-hepcidin-ferroportin axis in the liver, but less is known about this role in AKI.
  
  
  RESULTS
  By proteomics, we identified a 42 kDa soluble hemojuvelin (sHJV), processed by furin protease from membrane-bound hemojuvelin (mHJV), in the urine during AKI after cardiac surgery. Biopsies from human and mouse specimens with AKI confirm that HJV is extensively increased in renal tubules. Iron overload enhanced the expression of hemojuvelin-hepcidin signaling pathway. The furin inhibitor (FI) decreases furin-mediated proteolytic cleavage of mHJV into sHJV and augments the mHJV/sHJV ratio after iron overload with hypoxia condition. The FI could reduce renal tubule apoptosis, stabilize hypoxic induced factor-1, prevent the accumulation of iron in the kidney, and further ameliorate ischemic-reperfusion injury. mHJV is associated with decreasing total kidney iron, secreting hepcidin, and promoting the degradation of ferroportin at AKI, whereas sHJV does the opposite.
  
  
  METHODS
  This study suggests the ratio of mHJV/sHJV affects the iron deposition during acute kidney injury and sHJV could be an early biomarker of AKI.
  
  
  CONCLUSIONS
  Our findings link endogenous HJV inextricably with renal iron homeostasis for the first time, add new significance to early predict AKI, and identify novel therapeutic targets to reduce the severity of AKI using the FI.
authors.affiliation: 1 Department of Surgery, National Taiwan University Hospital , Taipei, Taiwan .
authors.forename: Guang-Huar
authors.initials: GH
authors.lastname: Young
authors.forename: Tao-Min
authors.initials: TM
authors.lastname: Huang
authors.forename: Che-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Lai
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Hou
authors.forename: Kang-Yung
authors.initials: KY
authors.lastname: Peng
authors.forename: Chan-Jung
authors.initials: CJ
authors.lastname: Liang
authors.forename: Shuei-Liong
authors.initials: SL
authors.lastname: Lin
authors.forename: Shih-Chung
authors.initials: SC
authors.lastname: Chang
authors.forename: Pi-Ru
authors.initials: PR
authors.lastname: Tsai
authors.forename: Kwan-Dun
authors.initials: KD
authors.lastname: Wu
authors.forename: Vin-Cent
authors.initials: VC
authors.lastname: Wu
authors.forename: Wen-Je
authors.initials: WJ
authors.lastname: Ko
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000652:urine*; D000209:Acute-Phase Proteins / Q000652:urine; D000818:Animals; D017209:Apoptosis; D006348:Cardiac Surgical Procedures / Q000009:adverse effects; D016022:Case-Control Studies; D002460:Cell Line; D045683:Furin / Q000037:antagonists & inhibitors / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000502:physiology*; D000071020:Hemochromatosis Protein; D006801:Humans; D007501:Iron / Q000502:physiology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications / Q000209:etiology / Q000652:urine*; D011507:Proteinuria / Q000209:etiology / Q000652:urine*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
chemical_list: D000209:Acute-Phase Proteins; D058851:GPI-Linked Proteins; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D015842:Serine Proteinase Inhibitors; D007501:Iron; D045683:Furin
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