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Molecular and Cellular Biology, March 2002, p. 1893-1902, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1893-1902.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Apolipoprotein J/Clusterin Prevents a Progressive Glomerulopathy of Aging

Mark E. Rosenberg,1* Richard Girton,1 David Finkel,1 David Chmielewski,1 Arthur Barrie III,2 David P. Witte,2 Guang Zhu,2 John J. Bissler,2 Judith A. K. Harmony,2 and Bruce J. Aronow2*

University of Minnesota, Minneapolis, Minnesota 55455,1 Children's Hospital Research Foundation, Cincinnati, Ohio 452422

Received 21 May 2001/ Returned for modification 31 October 2001/ Accepted 4 December 2001

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.

* Corresponding author. Mailing address for Mark E. Rosenberg: Division of Renal Diseases and Hypertension, Department of Medicine, University of Minnesota, UMHC 736, 516 Delaware St. S.E., Minneapolis, MN 55455. Phone: (612) 624-2603. Fax: (612) 626-3840. E-mail: rosen001{at}umn.edu. Mailing address for Bruce J. Aronow: Division of Molecular and Developmental Biology, Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45242. Phone: (513) 636-4865. Fax: (513) 636-4865. E-mail: bruce.aronow{at}chmcc.org.

Molecular and Cellular Biology, March 2002, p. 1893-1902, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1893-1902.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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