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Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination.
Dong, Wei; Wang, Hongjie; Shahzad, Khurrum; Bock, Fabian; Al-Dabet, Moh'd Mohanad; Ranjan, Satish; Wolter, Juliane; Kohli, Shrey; Hoffmann, Juliane; Dhople, Vishnu Mukund; Zhu, Cheng; Lindquist, Jonathan A; Esmon, Charles T; Gröne, Elisabeth; Gröne, Herman-Josef; Madhusudhan, Thati; Mertens, Peter R; Schlüter, Dirk; Isermann, Berend.
Afiliación
  • Dong W; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
  • Wang H; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
  • Shahzad K; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Department of Molecular Genetics, University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore, Pakistan;
  • Bock F; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
  • Al-Dabet MM; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
  • Ranjan S; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
  • Wolter J; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
  • Kohli S; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
  • Hoffmann J; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
  • Dhople VM; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany;
  • Zhu C; Department of Nephrology and Hypertension, Diabetes and Endocrinology, and.
  • Lindquist JA; Department of Nephrology and Hypertension, Diabetes and Endocrinology, and.
  • Esmon CT; Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and.
  • Gröne E; Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
  • Gröne HJ; Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
  • Madhusudhan T; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty.
  • Mertens PR; Department of Nephrology and Hypertension, Diabetes and Endocrinology, and.
  • Schlüter D; Institute of Microbiology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany;
  • Isermann B; Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, berend.isermann@med.ovgu.de berend_isermann@yahoo.de.
J Am Soc Nephrol ; 26(11): 2789-99, 2015 Nov.
Article en En | MEDLINE | ID: mdl-26015455
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Proteína C / Daño por Reperfusión / Ubiquitinación / Riñón Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Proteína C / Daño por Reperfusión / Ubiquitinación / Riñón Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos