Growth Arrest-Specific Protein 1 Is a Novel Endogenous Inhibitor of Glomerular Cell Activation and Proliferation

Kidney Int. 2013 Feb;83(2):251-63. doi: 10.1038/ki.2012.400. Epub 2012 Dec 19.

Abstract

Growth arrest-specific protein-1 (GAS1) is a GPI-anchored protein which is highly expressed in embryonic mouse fibroblasts and inhibits their proliferation. Glomerular mesangial cells release soluble GAS1 protein into the supernatant in vitro. Growth arrest led to GAS1 overexpression and increased release. Secretion involved disintegrin and metalloproteinase 10 and 17 as signified by inhibition experiments. Recombinant soluble GAS1 protein inhibited the proliferation of mesangial cells. Conversely, the induction of mesangial cell proliferation by PDGF-BB or -DD led to downregulation of GAS1 mRNA. Specific ligands of the PDGF α-receptor, PDGF-AA and -CC, had no effect. The GAS1 protein was localized in podocytes in kidneys from healthy rats. During the time course of mesangioproliferative glomerulonephritis in anti-Thy1.1-treated rats, glomerular GAS1 expression decreased prior to the onset of mesangial cell proliferation and increased at later stages during glomerular recovery. Finally, a plasmid expressing soluble GAS1 fused to an Fc fragment was systemically overexpressed in rats with mesangioproliferative glomerulonephritis. This ameliorated renal damage was indicated by decreased albuminuria and serum creatinine. Gas1/Fc-transfected rats also exhibited a reduction of the glomerular mesangial cell activation and proliferation. Thus, GAS1 is a novel endogenous inhibitor of glomerular mesangial cell proliferation and may be a novel therapeutic target in mesangioproliferative glomerular diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / physiology
  • ADAM10 Protein
  • ADAM17 Protein
  • Amyloid Precursor Protein Secretases / physiology
  • Animals
  • Becaplermin
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology*
  • Cell Proliferation
  • Cells, Cultured
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / physiology
  • Humans
  • Isoantibodies / pharmacology
  • Lymphokines / pharmacology
  • Membrane Proteins / physiology
  • Mesangial Cells / physiology*
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Platelet-Derived Growth Factor / pharmacology
  • Podocytes / metabolism
  • Proto-Oncogene Proteins c-sis / pharmacology
  • Rats

Substances

  • Cell Cycle Proteins
  • GAS1 protein, human
  • GPI-Linked Proteins
  • Isoantibodies
  • Lymphokines
  • Membrane Proteins
  • PDGFD protein, human
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • anti-Thy antibody
  • Becaplermin
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human
  • ADAM17 Protein