1. Endostatin and transglutaminase 2 are involved in fibrosis of the aging kidney.
- Author
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Lin CH, Chen J, Zhang Z, Johnson GV, Cooper AJ, Feola J, Bank A, Shein J, Ruotsalainen HJ, Pihlajaniemi TA, and Goligorsky MS
- Subjects
- Animals, Cells, Cultured, Cellular Senescence drug effects, Collagen Type XVIII genetics, Collagen Type XVIII pharmacology, Endostatins genetics, Endostatins pharmacology, Endothelial Cells, Extracellular Matrix Proteins, Fibrosis, Folic Acid toxicity, GTP-Binding Proteins genetics, GTP-Binding Proteins pharmacology, Kidney drug effects, Kidney metabolism, Kidney Diseases chemically induced, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Glutamine gamma Glutamyltransferase 2, Transglutaminases genetics, Transglutaminases pharmacology, Up-Regulation, Aging metabolism, Collagen Type XVIII metabolism, Endostatins metabolism, GTP-Binding Proteins metabolism, Kidney pathology, Kidney Diseases pathology, Transglutaminases metabolism
- 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., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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