Endostatin and transglutaminase 2 are involved in fibrosis of the aging kidney

Kidney Int. 2016 Jun;89(6):1281-92. doi: 10.1016/j.kint.2016.01.030. Epub 2016 Apr 14.

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.

Keywords: aging kidney; collagen XVIII; endostatin; fibrosis; tissue transglutaminase.

MeSH terms

  • Aging / metabolism*
  • Animals
  • Cells, Cultured
  • Cellular Senescence / drug effects
  • Collagen Type XVIII / genetics
  • Collagen Type XVIII / metabolism*
  • Collagen Type XVIII / pharmacology
  • Endostatins / genetics
  • Endostatins / metabolism*
  • Endostatins / pharmacology
  • Endothelial Cells
  • Extracellular Matrix Proteins
  • Fibrosis
  • Folic Acid / toxicity
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • GTP-Binding Proteins / pharmacology
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology*
  • Kidney Diseases / chemically induced
  • Kidney Diseases / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases / genetics
  • Transglutaminases / metabolism*
  • Transglutaminases / pharmacology
  • Up-Regulation

Substances

  • Collagen Type XVIII
  • Endostatins
  • Extracellular Matrix Proteins
  • Folic Acid
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins