title: Growth arrest-specific protein 1 is a novel endogenous inhibitor of glomerular cell activation and proliferation.
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.
authors.affiliation: Division of Nephrology, RWTH University Hospital Aachen, Aachen, Germany. cvanroeyen@ukaachen.de
authors.forename: Claudia R C
authors.initials: CR
authors.lastname: van Roeyen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zok
authors.forename: Jessica
authors.initials: J
authors.lastname: Pruessmeyer
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Nagayama
authors.forename: Stefan
authors.initials: S
authors.lastname: Fleckenstein
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
mesh_terms: D051722:ADAM Proteins / Q000502:physiology; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology; D000818:Animals; D000077214:Becaplermin; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D058851:GPI-Linked Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D007518:Isoantibodies / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology; D008565:Membrane Proteins / Q000502:physiology; D050527:Mesangial Cells / Q000502:physiology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D050199:Podocytes / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D051381:Rats
chemical_list: D018797:Cell Cycle Proteins; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins; D007518:Isoantibodies; D008222:Lymphokines; D008565:Membrane Proteins; C427493:PDGFD protein, human; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C035678:anti-Thy antibody; D000077214:Becaplermin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein