We evaluated the effect of the novel immunosuppressive agent, FK506, which is known to inhibit T cell immunity, on the development of lupus nephritis in MRL/MpJ-lpr/lpr (MRL/l) mice. FK506 was administered subcutaneously (1 mg/kg body weight) from 12 to 20 weeks of age in 13 MRL/l mice with spontaneous lupus nephritis. Nine animals receiving no treatment were used as the control. FK506 significantly reduced the development of proteinuria, lowered the level of BUN, and suppressed the elevation of serum anti-dsDNA antibodies. Histopathological study showed that FK506 significantly inhibited the progression of glomerular hypercellularity and crescent formation. Glomerular deposition of C3 was significantly reduced in the FK506-treated mice compared to the nontreated controls. These findings suggest that FK506 may protect against progression of lupus nephritis in MRL/1 mice, an animal model of systemic lupus erythematosus.

Platelet-derived growth factor (PDGF) plays an important role in the pathogenesis of mesangial proliferative glomerulonephritis. We examined PDGF expression and glomerular changes in lupus nephritis-prone MRL/MpJ-lpr/lpr (MRL/l) mice. The total number of nuclei per glomerular section and blood urea nitrogen (BUN) level were significantly increased in MRL/l mice aged 20 weeks compared to those aged 8 weeks. A positive correlation existed between numbers of PDGF β-chain-positive cells and glomerular cells in MRL/l mice (r = 0.77, p < 0.01). The BUN level did not differ among MRL/MP-++ (MRL/ n) mice of different ages, but the glomerular cell number increased modestly with age. At the age of 20 weeks, the incidence of crescent formation per kidney tissue ranged from 9 to 32% (mean 19%) in MRL/l mice but was 0 in MRL/n mice. PDGF β-chain protein was expressed in the mesangium and crescents in 20-week-old MRL/l mice but was expressed rarely in the glomeruli of MRL/n mice. These results suggest that the PDGF β-chain plays an important role in glomerular cell proliferation and crescent formation in murine lupus nephritis.

Platelet-activating factor (PAF) is known as an important mediator in the pathogenesis of glomerular injury. In the present study, we evaluated the effect of the specific PAF antagonists CV-6209 and CV-3988 on accelerated nephrotoxic serum nephritis (NTN) in the rat. The amount of urinary protein excretion was significantly less in the rats treated with CV-6209 or CV-3988 on the 5th and 7th day of treatment than in the nontreated controls. The results of light- and immunofluorescence-microscopic examination did not demonstrate any favorable effect on glomerular changes by these PAF antagonists. However, CV-6209 protected against the loss of glomerular anionic charges in rats with NTN. Thus, it is suggested that PAF is a potent mediator of protein excretion, and that the loss of glomerular anionic charges is an important mechanism for the mediation of PAF in glomerulonephritis.