title: Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis.
abstract: ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and.
authors: Anna
authors: A
authors: Bertram
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and.
authors: Svjetlana
authors: S
authors: Lovric
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and.
authors: Alissa
authors: A
authors: Engel
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and.
authors: Michaela
authors: M
authors: Beese
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and.
authors: Kristin
authors: K
authors: Wyss
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and.
authors: Barbara
authors: B
authors: Hertel
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and.
authors: Joon-Keun
authors: JK
authors: Park
authors: Institute for Forensic Medicine, Hannover Medical School, Hannover, Germany; and.
authors: Jan U
authors: JU
authors: Becker
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and.
authors: Johanna
authors: J
authors: Kegel
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and.
authors: Hermann
authors: H
authors: Haller
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and Medical Clinic III, Klinikum Fulda, Fulda, Germany.
authors: Marion
authors: M
authors: Haubitz
authors: Department of Nephrology and Hypertension, Center for Internal Medicine and Kirsch.Torsten@mh-hannover.de.
authors: Torsten
authors: T
authors: Kirsch
mesh_terms: D051722:ADAM Proteins / Q000097:blood*; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007118:Immunoassay; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000378:metabolism; D008875:Middle Aged; D053146:Myeloblastin / Q000097:blood / Q000276:immunology*; D010641:Phenotype
chemical_list: D016207:Cytokines; C508600:IL6 protein, human; D015850:Interleukin-6; C000599270:MIRN-634 microRNA, human; D035683:MicroRNAs; D053146:Myeloblastin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: ANCA; cardiovascular disease; cytokines; endothelium; macrophages; vasculitis