Murine lupus nephritis. Effects of glucocorticoid on glomerular permeability

We investigated the effects of methylprednisolone on the glomerular permeability of mice with lupus nephritis. At the onset of nephritis, the mice were divided into two groups: one group was injected with methylprednisolone and the other with saline; treatment continued for 12 weeks. We determined the protein concentration in specimens of urine collected every 2 weeks, and pre- and posttherapy urine samples were analyzed by electrophoresis. After 12 weeks, we injected anionic or cationized ferritin systemically into mice of each group and studied kidney samples by electron microscopy. At the onset of nephritis (5 months of age), proteinuria (5.2 mg/day) was selective and albumin was the predominant (87%) protein excreted. Electron-dense deposits were then confined to mesangial areas. In untreated mice, protein excretion values doubled at 5.5 months of age, tripled at 6 months of age, and increased 5-, 7-, 9-, and 11-fold at subsequent intervals of 2 weeks, to reach 55.0 mg/day at 8 months of age. Proteinuria was poorly selective, and protein excretion values correlated inversely with survival rate (35% at the end of study). The glomerular basement membranes were studded with electron-dense deposits and were depleted in anionic sites, as judged by decreased binding of cationized ferritin molecules. The anionic ferritin molecules permeated the basement membrane at the vicinity of electron-dense deposits and reached the urinary space through residual slit pores. In methylprednisolone-treated mice, by contrast, protein excretion values were low, proteinuria was selective, and remained virtually unchanged at 5.3 mg/day by 8 months of age. There were no deaths in this group. Most of the electron-dense deposits were present in mesangia. Anionic sites of the glomerular basement membranes were largely preserved and anionic ferritin molecules were mostly limited to the luminal aspect of the basement membrane. These studies suggest that methylprednisolone therapy preserved glomerular permeability characteristics by decreasing the localization of immunoreactants in glomeruli and by interfering with factors that favor the localization of immune complexes in the capillary wall.