Mycophenolic acid reduces matrix synthesis in human mesangial cells stimulated with anti-DNA antibodies

Abstract

Lupus nephritis is an important cause of acute or chronic renal failure. There is accumulating data to show that combined use of mycophenolate mofetil (MMF) and corticosteroid is an effective treatment for severe lupus nephritis. While the efficacy of MMF relates primarily to the inhibition of lymphocyte proliferation, there is preliminary evidence that it may have a direct effect on mesangial cells. We have thus investigated the actions of mycophenolic acid (MPA), the active metabolite of MMF, on human mesangial cells (HMC) stimulated with anti-DNA antibodies. Polyclonal anti-DNA antibodies were isolated from 12 patients with active diffuse proliferative lupus nephritis by affinity chromatography. Incubation of HMC with anti-DNA antibodies (10 μg/ml IgG concentration) for up to 96 h increased cell proliferation (p<0.05) and induced fibronectin, thrombospondin-1 and collagen type I synthesis in a time-dependent manner, compared with normal human IgG (p<0.05 for all). These changes were not observed with the non-anti-DNA immunoglobulin fractions of the corresponding sera, and were preceded by anti-DNA antibody induced TGF-β1 secretion and PKC-α activation. Concomitant addition of MPA (0-10 μM) and anti-DNA antibodies to HMC resulted in dose-dependent amelioration of the induced cell proliferation, which was significant after 48 h with an MPA concentration of ≥0.01 μM (p<0.05). MPA also significantly reduced fibronectin, thrombospondin-1 and collagen type I synthesis and deposition in the extracellular milieu, by abrogating TGF-β1 bioactivation and reducing activation of PKC-α. These effects of MPA on HMC in the presence of anti-DNA antibodies were reversible. We conclude that MPA can reduce anti-DNA antibody induced HMC proliferation and synthesis of matrix components, and these actions may contribute to the efficacy of MMF in the treatment of lupus nephritis.