title: α2AP mediated myofibroblast formation and the development of renal fibrosis in unilateral ureteral obstruction.
abstract: Renal fibrosis is the final common pathway of a wide variety of chronic kidney diseases. Myofibroblast formation via the differentiation of from tissue-resident fibroblasts and bone marrow-derived mesenchymal stem cells (MSCs), and epithelial-to-mesenchymal transition (EMT) is known to play a pivotal role in the development of renal fibrosis. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated the role of alpha 2-antiplasmin (α2AP) in myofibroblast formation and the development of renal fibrosis. We observed the development of renal fibrosis using unilateral ureteral obstruction (UUO). α2AP had accumulated in the UUO-induced obstructed kidneys and α2AP deficiency attenuated UUO-induced renal fibrosis in mice. The degree of myofibroblast formation in the obstructed kidneys of α2AP(-/-) mice was less than that in α2AP(+/+) mice. In vitro, α2AP induced myofibroblast formation in renal tubular epithelial cells (RTECs), renal fibrosblasts, and bone marrow-derived mesenchymal stem cells (MSCs). α2AP also induced the production of TGF-β, which is known to be a key regulator of myofibroblast formation and fibrosis. α2AP-induced the TGF-β production was significantly reduced by SP600125, c-Jun N-terminal kinase (JNK) specific inhibitor. Our findings suggest that α2AP induces myofibroblast formation in the obstructed kidneys, and mediates the development of renal fibrosis.
authors.affiliation: Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's Collage of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto, 610-0395, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kanno
authors.affiliation: Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's Collage of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto, 610-0395, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Kawashita
authors.affiliation: Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's Collage of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto, 610-0395, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kokado
authors.affiliation: Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's Collage of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto, 610-0395, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kuretake
authors.affiliation: Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's Collage of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto, 610-0395, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Physiology II. Kinki University School of Medicine, Osaka-sayama, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okada
authors.affiliation: Department of Dermatology, Gifu University Graduate School of Medicine, Yanagido Gifu, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Seishima
authors.affiliation: 1] Department of Physiology II. Kinki University School of Medicine, Osaka-sayama, Japan [2] Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ueshima
authors.affiliation: Department of Physiology II. Kinki University School of Medicine, Osaka-sayama, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsuo
authors.affiliation: Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's Collage of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto, 610-0395, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsuno
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051437:Renal Insufficiency / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014513:Ureter / Q000378:metabolism / Q000473:pathology; D014517:Ureteral Obstruction / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000979:alpha-2-Antiplasmin / Q000172:deficiency / Q000235:genetics*
chemical_list: D000873:Anthracenes; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; D000979:alpha-2-Antiplasmin; C432165:pyrazolanthrone; D048670:MAP Kinase Kinase 4
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