SPARC Regulates Cell Cycle Progression in Mesangial Cells via Its Inhibition of IGF-dependent Signaling

J Cell Biochem. 2003 Mar 1;88(4):802-11. doi: 10.1002/jcb.10424.

Abstract

Glomerular mesangial cells both synthesize and respond to insulin-like growth factor-1 (IGF-1). Increased activity of the IGF signaling pathway has been implicated as a major contributor to renal enlargement and subsequent development of diabetic nephropathy. Secreted protein acidic and rich in cysteine (SPARC), a matricellular protein, has been shown to modulate the interaction of cells with growth factors and extracellular matrix. We have reported that primary glomerular mesangial cells derived from SPARC-null mice exhibit an accelerated rate of proliferation and produce substantially decreased levels of transforming growth factor beta1 (TGF-beta1) in comparison to their wild-type counterparts (Francki et al. [1999] J. Biol. Chem. 274: 32145-32152). Herein we present evidence that SPARC modulates IGF-dependent signaling in glomerular mesangial cells. SPARC-null mesangial cells produce increased amounts of IGF-1 and -2, as well as IGF-1 receptor (IGF-1R) in comparison to wild-type cells. Addition of recombinant SPARC to SPARC-null cells inhibited IGF-1-stimulated mitogen activated protein kinase (MAPK) activation and DNA synthesis. We also show that the observed accelerated rate of basal and IGF-1-stimulated proliferation in mesangial cells derived from SPARC-null animals is due, at least in part, to markedly diminished levels of cyclin D1 and the cyclin-dependent kinase (cdk) inhibitors p21 and p27. Since expression of SPARC in the glomerulus is especially prominent during renal injury, our findings substantiate previous claims that SPARC is involved in glomerular remodeling and repair, a process commonly associated with mesangioproliferative glomerulonephritis and diabetic nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Cycle Proteins / biosynthesis
  • Cell Division / drug effects
  • Cells, Cultured
  • Diabetic Nephropathies / physiopathology
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / physiology*
  • Glomerulonephritis / physiopathology
  • Insulin-Like Growth Factor I / antagonists & inhibitors
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor II / biosynthesis
  • Mice
  • Osteonectin / deficiency
  • Osteonectin / pharmacology
  • Osteonectin / physiology*
  • Protein Kinase Inhibitors
  • Protein Kinases / biosynthesis
  • RNA / analysis
  • RNA / biosynthesis
  • RNA, Messenger / analysis
  • RNA, Messenger / biosynthesis
  • Receptor, IGF Type 1 / biosynthesis
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta1

Substances

  • Cell Cycle Proteins
  • Osteonectin
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • RNA
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Protein Kinases
  • Receptor, IGF Type 1