Progression to
chronic renal failure varies between patients with
lupus nephritis. We compared the effects of
mycophenolate mofetil (MMF) and
cyclophosphamide (CTX), on renal histology and cellular pathways of
fibrosis in murine
lupus nephritis. Female NZBWF1/J mice were randomized to treatment with vehicle,
methylprednisolone (MP) alone, MMF + MP or CTX + MP for up to 12 weeks, and the effects on clinical parameters, renal histology, and fibrotic processes were investigated. Treatment with MMF + MP or CTX + MP both improved survival, renal function, and decreased
anti-dsDNA antibody level and
immune complex deposition in kidneys of mice with active
nephritis. Vehicle-treated mice showed progressive increase in mesangial proliferation, inflammatory cell infiltration and renal tubular
atrophy, associated with PKC-α activation, increased TGF-β1 expression and increased matrix
protein deposition. MP treatment alone did not have any significant effect. MMF + MP or CTX + MP treatment for 12 weeks reduced these abnormalities. MMF + MP was more effective than CTX + MP in suppressing fibrotic mediators, histological
fibrosis score and expression of TGF-β1,
fibronectin and
collagen I in the kidney. Results from in vitro experiments on human mesangial cells (HMC) showed that
mycophenolic acid (MPA) was more effective than CTX in suppressing PKC-α activation and TGF-β1 secretion induced by human polyclonal
anti-dsDNA antibodies. While both MPA and CTX decreased TGF-β1- and TNF-α-induced
fibronectin synthesis, only MPA decreased
IL-6 induced
fibronectin synthesis. MPA and CTX show distinct effects on fibrotic and inflammatory processes in NZBWF1/J murine
lupus nephritis, suggesting that MMF + MP may be more effective than CTX + MP in preserving normal renal histology in
lupus nephritis.