Clusterin is up-regulated in glomerular mesangial cells in complement-mediated injury
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Published on: August 19, 2020
1Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan.
Insights
Clusterin is upregulated in glomerular mesangial cells during immune-mediated kidney injury, suggesting a protective role against complement attack. This finding clarifies the source of clusterin in nephropathy.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Clusterin is a complement regulatory protein involved in inhibiting the membrane attack complex (C5b-9).
- Glomerular clusterin deposition is noted in membranous nephropathy, but its cellular origin remains debated.
- This study investigates whether resident glomerular cells express clusterin during complement-mediated injury.
Purpose of the Study:
- To determine if glomerular mesangial cells express clusterin when subjected to complement-mediated injury.
- To elucidate the cellular source of clusterin in the glomerulus during immune-mediated kidney disease.
Main Methods:
- In vitro: Cultured rat mesangial cells were stimulated with antithymocyte globulin and complement.
- In vivo: Anti-Thy1 nephritis was induced in rats, with kidney analysis on days 8 and 29.
Main Results:
- Sublytic complement attack increased clusterin expression in cultured mesangial cells.
- Rats with anti-Thy1 nephritis showed increased glomerular clusterin mRNA and mesangial protein deposition.
- Clusterin deposition correlated with C5b-9 deposition in the glomeruli of affected rats.
Conclusions:
- Clusterin is induced in glomerular mesangial cells during immune-mediated kidney injury.
- This upregulation of clusterin may serve a protective function for mesangial cells against complement-mediated damage.
Background:
Clusterin is a soluble complement regulatory protein that binds to C5b-7 and inhibits generation of membrane attack complex, C5b-9. Glomerular deposition of clusterin has been observed in human and experimental membranous nephropathy in association with C5b-9 and immune deposits. However, it is controversial as to whether clusterin observed in glomeruli is synthesized by the resident glomerular cells or is derived from the circulation. We examined whether clusterin is expressed by resident glomerular cells exposed to complement-mediated injury.
Methods:
In vitro, cultured mesangial cells were exposed to antithymocyte serum immunoglobulin G and 5% normal rat serum as a complement source. In vivo, we induced anti-Thy1 nephritis in rats and examined the kidneys on days 8 and 29.
Results:
We observed increased expression of clusterin in cultured rat glomerular mesangial cells stimulated by sublytic complement attack. We also demonstrated that in comparison with control rats, both a marked increase in clusterin mRNA in the glomeruli and marked deposition of clusterin protein in the mesangial area occurred in the OX-7-treated rats on day 8 in association with C5b-9 deposition and on day 29.
Conclusion:
Clusterin was induced in glomerular mesangial cells during the course of immune-mediated injuries. This up-regulation of clusterin may play a critical role in protecting mesangial cells from complement attack.
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