title: Endostatin and transglutaminase 2 are involved in fibrosis of the aging kidney.
abstract: Endostatin (EST), an antiangiogenic factor, is enriched in aging kidneys. EST is also an interactive partner of transglutaminase 2 (TG2), an enzyme that cross-links extracellular matrix proteins. Here we tested whether EST and TG2 play a role in the fibrosis of aging. In wild-type mice, aging kidneys exhibited a 2- to 4-fold increase in TG2 paralleled by increased cross-linked extracellular matrix proteins and fibrosis. Mice transgenic to express EST showed renal fibrosis at a young age. One-month delivery of EST via minipumps to young mice showed increased renal fibrosis that became more robust when superimposed on folic acid-induced nephropathy. Upregulated TG2 and impaired renal function were apparent with EST delivery combined with folic acid-induced nephropathy. Subcapsular injection of TG2 and/or EST into kidneys of young mice not only induced interstitial fibrosis, but also increased the proportion of senescent cells. Thus, kidney fibrosis in aging may represent a natural outcome of upregulated EST and TG2, but more likely it appears to be a result of cumulative stresses occurring on the background of synergistically acting geronic (aging) proteins, EST and TG2.
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Pharmacology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Chi Hua Sarah
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Pharmacology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.
authors.forename: Zhongtao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, University of Rochester, Rochester, New York, USA.
authors.forename: Gail V W
authors.initials: GV
authors.lastname: Johnson
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.
authors.forename: Arthur J L
authors.initials: AJ
authors.lastname: Cooper
authors.affiliation: Department of Anesthesiology, University of Rochester, Rochester, New York, USA.
authors.forename: Julianne
authors.initials: J
authors.lastname: Feola
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Pharmacology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bank
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Pharmacology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shein
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Heli J
authors.initials: HJ
authors.lastname: Ruotsalainen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Taina A
authors.initials: TA
authors.lastname: Pihlajaniemi
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Pharmacology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA. Electronic address: Michael_goligorsky@nymc.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D043170:Collagen Type XVIII / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D043169:Endostatins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D042783:Endothelial Cells; D016326:Extracellular Matrix Proteins; D005355:Fibrosis; D005492:Folic Acid / Q000633:toxicity; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D043170:Collagen Type XVIII; D043169:Endostatins; D016326:Extracellular Matrix Proteins; D005492:Folic Acid; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: aging kidney; collagen XVIII; endostatin; fibrosis; tissue transglutaminase