A Novel, Dual Role of CCN3 in Experimental Glomerulonephritis: Pro-Angiogenic and Antimesangioproliferative Effects

Am J Pathol. 2012 May;180(5):1979-90. doi: 10.1016/j.ajpath.2012.01.031.

Abstract

In contrast to factors that promote mesangial cell proliferation, little is known about their endogenous inhibitors. During experimental mesangioproliferative nephritis, expression of the glomerular CCN3 (nephroblastoma overexpressed gene [NOV]) gene is reduced before the proliferative phase and increased in glomeruli and serum when mesangial cell proliferation subsides. To further elucidate its role in mesangioproliferative glomerulonephritis, CCN3 systemically was overexpressed by muscle electroporation in healthy or nephritic rats. This increased CCN3 serum concentrations more than threefold for up to 56 days. At day 5 after disease induction, CCN3-transfected rats showed an increase in glomerular endothelial area and in mRNA levels of the pro-angiogenic factors vascular endothelial growth factor and PDGF-C. At day 7, CCN3 overexpression decreased mesangial cell proliferation, including expression of α-smooth muscle actin and matrix accumulation of fibronectin and type IV collagen. In progressive nephritis (day 56), overexpression of CCN3 resulted in decreased albuminuria, glomerulosclerosis, and reduced cortical collagen type I accumulation. In healthy rat kidneys, overexpression of CCN3 induced no morphologic changes but regulated glomerular gene transcripts (reduced transcription of PDGF-B, PDGF-D, PDGF-receptor-β, and fibronectin, and increased PDGF-receptor-α and PDGF-C mRNA). These data identify a dual role for CCN3 in experimental glomerulonephritis with pro-angiogenic and antimesangioproliferative effects. Manipulation of CCN3 may represent a novel approach to help repair glomerular endothelial damage and mesangioproliferative changes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Acute Disease
  • Angiogenesis Inducing Agents / metabolism
  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Collagen Type IV / metabolism
  • Disease Progression
  • Electrochemotherapy / methods
  • Endothelial Cells / drug effects
  • Fibronectins / metabolism
  • Genetic Therapy / methods
  • Glomerular Mesangium / pathology
  • Glomerulonephritis, Membranoproliferative / metabolism*
  • Glomerulonephritis, Membranoproliferative / pathology
  • Glomerulonephritis, Membranoproliferative / physiopathology
  • Glomerulonephritis, Membranoproliferative / therapy
  • Humans
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / drug effects
  • Male
  • Mesangial Cells / pathology
  • Muscle, Skeletal / metabolism
  • Neovascularization, Physiologic / physiology*
  • Nephroblastoma Overexpressed Protein / blood
  • Nephroblastoma Overexpressed Protein / genetics
  • Nephroblastoma Overexpressed Protein / pharmacology
  • Nephroblastoma Overexpressed Protein / physiology*
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar
  • Real-Time Polymerase Chain Reaction / methods
  • Recombinant Proteins / pharmacology

Substances

  • Actins
  • Angiogenesis Inducing Agents
  • Collagen Type IV
  • Fibronectins
  • Nephroblastoma Overexpressed Protein
  • RNA, Messenger
  • Recombinant Proteins
  • smooth muscle actin, rat