Apolipoprotein J/clusterin prevents a progressive glomerulopathy of aging

Mol Cell Biol. 2002 Mar;22(6):1893-902. doi: 10.1128/MCB.22.6.1893-1902.2002.

Abstract

Apoliprotein J (apoJ)/clusterin has attracted considerable interest based on its inducibility in multiple injury processes and accumulation at sites of remodeling, regression, and degeneration. We therefore sought to investigate apoJ/clusterin's role in kidney aging, as this may reveal the accumulated effects of diminished protection. Aging mice deficient in apoJ/clusterin developed a progressive glomerulopathy characterized by the deposition of immune complexes in the mesangium. Up to 75% of glomeruli in apoJ/clusterin-deficient mice exhibited moderate to severe mesangial lesions by 21 months of age. Wild-type and hemizygous mice exhibited little or no glomerular pathology. In the apoJ/clusterin-deficient mice, immune complexes of immunoglobulin G (IgG), IgM, IgA, and in some cases C1q, C3, and C9 were detectable as early as 4 weeks of age. Electron microscopy revealed the accumulation of electron-dense material in the mesangial matrix and age-dependent formation of intramesangial tubulo-fibrillary structures. Even the most extensively damaged glomeruli showed no evidence of inflammation or necrosis. In young apoJ/clusterin-deficient animals, the development of immune complex lesions was accelerated by unilateral nephrectomy-induced hyperfiltration. Injected immune complexes localized to the mesangium of apoJ/clusterin-deficient but not wild-type mice. These results establish a protective role of apoJ/clusterin against chronic glomerular kidney disease and support the hypothesis that apoJ/clusterin modifies immune complex metabolism and disposal.

Publication types

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

MeSH terms

  • Aging / pathology*
  • Animals
  • Antigen-Antibody Complex / metabolism*
  • Clusterin
  • Complement System Proteins / metabolism
  • Disease Progression
  • Glomerular Mesangium / metabolism
  • Glomerular Mesangium / pathology
  • Glomerular Mesangium / ultrastructure
  • Glomerulonephritis, Membranoproliferative / genetics
  • Glomerulonephritis, Membranoproliferative / metabolism
  • Glomerulonephritis, Membranoproliferative / pathology*
  • Glycoproteins / deficiency*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Heterozygote
  • Homozygote
  • Immunoglobulins / metabolism
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / ultrastructure
  • Mice
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Nephrectomy

Substances

  • Antigen-Antibody Complex
  • Clu protein, mouse
  • Clusterin
  • Glycoproteins
  • Immunoglobulins
  • Molecular Chaperones
  • Complement System Proteins