title: Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-β signaling in chronic kidney disease.
abstract: Renal fibrosis is a common pathological consequence of chronic kidney disease (CKD) with tissue fibrosis closely associated with chronic inflammation in numerous pathologies. However, molecular mechanisms underlying that association, particularly in the kidney, remain unclear. Here, we determine whether there is a molecular link between chronic inflammation and tissue fibrosis in CKD progression. Histological analysis of human kidneys indicated abundant expression of angiopoietin-like protein 2 (ANGPTL2) in renal tubule epithelial cells during progression of renal fibrosis. Numerous ANGPTL2-positive renal tubule epithelial cells colocalized with cells positive for transforming growth factor (TGF)-β1, a critical mediator of tissue fibrosis. Analysis of M1 collecting duct cells in culture showed that TGF-β1 increases ANGPTL2 expression by attenuating its repression through microRNA-221. Conversely, ANGPTL2 increased TGF-β1 expression through α5β1 integrin-mediated activation of extracellular signal-regulated kinase. Furthermore, ANGPTL2 deficiency in a mouse unilateral ureteral obstruction model significantly reduced renal fibrosis by decreasing TGF-β1 signal amplification in kidney. Thus, ANGPTL2 and TGF-β1 positively regulate each other as renal fibrosis progresses. Our study provides insight into molecular mechanisms underlying chronic inflammation and tissue fibrosis and identifies potential therapeutic targets for CKD treatment.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan; Center for Clinical Research, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan; Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan. Electronic address: morijun@kumamoto-u.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Morinaga
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kadomatsu
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Terada
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Sugizaki
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanigawa
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Shunshun
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Sato
authors.affiliation: Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Kimi
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of Surgical Pathology, Kumamoto University Hospital, Chuo-ku, Kumamoto, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Iyama
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.affiliation: Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kitamura
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan. Electronic address: oike@gpo.kumamoto-u.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D007684:Kidney Tubules / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D039081:Integrin alpha5beta1; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; C485792:ANGPTL2 protein, human; C485793:Angptl2 protein, mouse; C525709:MIR221, human; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse
keywords: TGF-β; chronic kidney disease; fibrosis