Apolipoprotein J/clusterin prevents a progressive glomerulopathy of aging.
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.
Rosenberg
Mark E
ME
Division of Renal Diseases and Hypertension, Department of Medicine, University of Minnesota, UMHC 736, 516 Delaware Street SE, Minneapolis, MN 55455, USA. rosen001@umn.edu
Girton
Richard
R
Finkel
David
D
Chmielewski
David
D
Barrie
Arthur
A
Witte
David P
DP
Zhu
Guang
G
Bissler
John J
JJ
Harmony
Judith A K
JA
Aronow
Bruce J
BJ
D000375:Aging / Q000473:pathology*; D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D051152:Clusterin; D003165:Complement System Proteins / Q000378:metabolism; D018450:Disease Progression; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006023:Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D007136:Immunoglobulins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009392:Nephrectomy
D000936:Antigen-Antibody Complex; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D007136:Immunoglobulins; D018832:Molecular Chaperones; D003165:Complement System Proteins