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Published on: September 12, 2019
Effect of mycophenolate and rapamycin on renal fibrosis in lupus nephritis
Chenzhu Zhang1, Caleb C Y Chan1, Kwok Fan Cheung1
1Department of Medicine, The University of Hong Kong, The University of Hong Kong, Hong Kong.
Abstract:
Lupus nephritis (LN) leads to chronic kidney disease (CKD) through progressive fibrosis. Mycophenolate inhibits inosine monophosphate dehydrogenase and is a standard treatment for LN. The mammalian or mechanistic target of rapamycin (mTOR) pathway is activated in LN. Rapamycin inhibits mTOR and is effective in preventing kidney transplant rejection, with the additional merits of reduced incidence of malignancies and viral infections. The effect of mycophenolate or rapamycin on kidney fibrosis in LN has not been investigated. We investigated the effects of mycophenolate and rapamycin in New Zealand Black and White first generation (NZB/W F1) murine LN and human mesangial cells (HMCs), focusing on mechanisms leading to kidney fibrosis. Treatment of mice with mycophenolate or rapamycin improved nephritis manifestations, decreased anti-double stranded (ds) DNA antibody titer and reduced immunoglobulin G (IgG) deposition in the kidney. Both mycophenolate and rapamycin, especially the latter, decreased glomerular mTOR Ser2448 phosphorylation. Renal histology in untreated mice showed mesangial proliferation and progressive glomerulosclerosis with tubular atrophy, and increased expression of transforming growth factor β1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), α-smooth muscle actin (α-SMA), fibronectin (FN) and collagen. Both mycophenolate and rapamycin ameliorated the histopathological changes. Results from in vitro experiments showed that both mycophenolate and rapamycin decreased mesangial cell proliferation and their binding with anti-dsDNA antibodies. Mycophenolate and rapamycin also down-regulated mTOR and extracellular signal-regulated kinase (ERK) phosphorylation and inhibited fibrotic responses in mesangial cells that were induced by anti-dsDNA antibodies or TGF-β1. Our findings suggest that, in addition to immunosuppression, mycophenolate and rapamycin may reduce fibrosis in LN, which has important implications in preventing CKD in patients with LN.
Insights
Mycophenolate and rapamycin show potential in treating lupus nephritis (LN) by reducing kidney fibrosis. These drugs may help prevent chronic kidney disease (CKD) in LN patients beyond their immunosuppressive effects.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Lupus nephritis (LN) causes chronic kidney disease (CKD) via fibrosis.
- Mammalian target of rapamycin (mTOR) pathway is active in LN.
- Mycophenolate and rapamycin are used for LN and transplant rejection, respectively.
Purpose of the Study:
- Investigate mycophenolate and rapamycin effects on kidney fibrosis in murine LN and human mesangial cells (HMCs).
- Focus on mechanisms underlying kidney fibrosis development.
Main Methods:
- Treatment of NZB/W F1 mice and HMCs with mycophenolate or rapamycin.
- Assessment of nephritis, autoantibodies, kidney histology, and fibrotic markers (TGF-β1, MCP-1, α-SMA, FN, collagen).
- Evaluation of mTOR and ERK phosphorylation in HMCs.
Main Results:
- Both drugs improved LN manifestations, reduced autoantibodies and IgG deposition.
- Mycophenolate and rapamycin decreased glomerular mTOR phosphorylation and ameliorated renal histology.
- In vitro, they reduced mesangial cell proliferation, anti-dsDNA binding, mTOR/ERK phosphorylation, and fibrotic responses.
Conclusions:
- Mycophenolate and rapamycin may reduce kidney fibrosis in LN through immunosuppression and direct antifibrotic mechanisms.
- These findings suggest a role in preventing CKD progression in LN patients.
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