Apolipoprotein J/Clusterin Prevents a Progressive Glomerulopathy of Aging

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 estab-lish a protective role of apoJ/clusterin against chronic glomerular kidney disease and support the hypothesis that apoJ/clusterin modifies immune complex metabolism and disposal. Apolipoprotein J (apoJ)/clusterin is a circulating glycopro-tein constitutively expressed by diverse epithelial cells. The protein is induced in injured organs in various disease states, such as Alzheimer's disease, atherosclerosis, myocardial infarc-tion, and multiple forms of acute and chronic renal disease (20, 25). Proposed functions for apoJ/clusterin include lipid trans-port, complement defense, regulation of apoptosis, membrane protection, and promotion of cell-cell interactions (25). ApoJ/ clusterin can bind a large number of macromolecules impli-cated in disease initiation and progression, including immuno-globulins and complement components. Recently clusterin has been demonstrated to function as a molecular chaperone, pre-venting denatured protein precipitation through binding to exposed hydrophobic regions and improving high-molecular-weight complex solubility (6). The structure of apoJ/clusterin has not provided much in-sight into function. Mammalian apoJ/clusterins are approxi-mately 80-kDa heterodimers (9, 16) consisting of two 40-kDa chains joined by a unique five-disulfide-bond motif (10). The protein has limited homology to other proteins and lacks clear functional motifs (9). It does contain three putative amphi-pathic ␣-helical regions, which could allow it to interact with lipids and hydrophobic regions of other proteins (6). We have recently shown that apoJ/clusterin-deficient mice exhibit enhanced inflammatory severity and sequelae in an autoimmune myocarditis model, suggesting that it can serve an anti-inflammatory role under some conditions (14). Given the marked upregulation of apoJ/clusterin that occurs in diverse tissue injury processes, it is likely that the effects of its absence in different models may reveal a variety of phenotypic features and manifestations. We hypothesized that if apoJ/clusterin played an important role in the management of inflammatory and apoptosis-associated protein complexes, there should be an accumulated effect of the failure to properly manage these proteins over time. Since free plasma protein and macromo-lecular complexes traffic through the mesangium of the kidney, this structure is particularly at risk for compromise by the absence of apoJ/clusterin. In this study, we demonstrate that the kidneys of apoJ/clusterin-deficient mice developed a pro-gressive glomerulopathy with age, characterized by mesangial expansion and the presence of deposits of immunoglobulins and complement components. These findings implicate a role for apoJ/clusterin in the long-term health of the kidney and suggest that it participates in a biochemical system for mesan-gial protection.