title: Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination.
abstract: Ischemia-reperfusion injury (IRI) is the leading cause of ARF. A pathophysiologic role of the coagulation system in renal IRI has been established, but the functional relevance of thrombomodulin (TM)-dependent activated protein C (aPC) generation and the intracellular targets of aPC remain undefined. Here, we investigated the role of TM-dependent aPC generation and therapeutic aPC application in a murine renal IRI model and in an in vitro hypoxia and reoxygenation (HR) model using proximal tubular cells. In renal IRI, endogenous aPC levels were reduced. Genetic or therapeutic reconstitution of aPC efficiently ameliorated renal IRI independently of its anticoagulant properties. In tubular cells, cytoprotective aPC signaling was mediated through protease activated receptor-1- and endothelial protein C receptor-dependent regulation of the cold-shock protein Y-box binding protein-1 (YB-1). The mature 50 kD form of YB-1 was required for the nephro- and cytoprotective effects of aPC in vivo and in vitro, respectively. Reduction of mature YB-1 and K48-linked ubiquitination of YB-1 was prevented by aPC after renal IRI or tubular HR injury. aPC preserved the interaction of YB-1 with the deubiquitinating enzyme otubain-1 and maintained expression of otubain-1, which was required to reduce K48-linked YB-1 ubiquitination and to stabilize the 50 kD form of YB-1 after renal IRI and tubular HR injury. These data link the cyto- and nephroprotective effects of aPC with the ubiquitin-proteasome system and identify YB-1 as a novel intracellular target of aPC. These insights may provide new impetus for translational efforts aiming to restrict renal IRI.
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Department of Molecular Genetics, University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore, Pakistan;
authors.forename: Khurrum
authors.initials: K
authors.lastname: Shahzad
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
authors.forename: Fabian
authors.initials: F
authors.lastname: Bock
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
authors.forename: Moh'd Mohanad
authors.initials: MM
authors.lastname: Al-Dabet
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
authors.forename: Satish
authors.initials: S
authors.lastname: Ranjan
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
authors.forename: Juliane
authors.initials: J
authors.lastname: Wolter
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
authors.forename: Shrey
authors.initials: S
authors.lastname: Kohli
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
authors.forename: Juliane
authors.initials: J
authors.lastname: Hoffmann
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany;
authors.forename: Vishnu Mukund
authors.initials: VM
authors.lastname: Dhople
authors.affiliation: Department of Nephrology and Hypertension, Diabetes and Endocrinology, and.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Nephrology and Hypertension, Diabetes and Endocrinology, and.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Lindquist
authors.affiliation: Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gröne
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Herman-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
authors.forename: Thati
authors.initials: T
authors.lastname: Madhusudhan
authors.affiliation: Department of Nephrology and Hypertension, Diabetes and Endocrinology, and.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
authors.affiliation: Institute of Microbiology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany;
authors.forename: Dirk
authors.initials: D
authors.lastname: Schlüter
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, berend.isermann@med.ovgu.de berend_isermann@yahoo.de.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
mesh_terms: D000483:Alleles; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D003433:Crosses, Genetic; D003546:Cysteine Endopeptidases / Q000235:genetics; D004195:Disease Models, Animal; D005091:Exons; D000860:Hypoxia / Q000473:pathology; D007668:Kidney / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010100:Oxygen / Q000737:chemistry; D011486:Protein C / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology*; D015398:Signal Transduction; D013927:Thrombosis / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000925:Anticoagulants; D003546:Cysteine Endopeptidases; D010100:Oxygen; D011486:Protein C; D014157:Transcription Factors; C541744:Ybx1 protein, mouse; C507756:Otub1 protein, mouse
keywords: acute renal; cell signaling; failure; ischemia-reperfusion; ischemic renal failure; renal proximal tubule cell; thrombosis