Effects of 1alpha,25-dihydroxyvitamin D3 on the MRL/MpJ-Fas/lpr model of systemic lupus erythematosus .

摘要

Systemic lupus erythematosus (SLE) is a chronic, relapsing autoimmune disease with multiple organ system involvement. Among the organs that are affected, the kidney is involved in approximately 60% of all SLE cases. Lupus nephritis is characterized by glomerular immune complex (IC) deposition, tubular inflammation and interstitial leukocyte infiltration. We investigated the effects of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the MRL/MpJ-Faslpr (MRL/lpr) murine model of SLE. We found that treating MRL/lpr mice with 300 ng 1,25(OH)2D3/day completely prevents proteinuria. Renal changes induced by 1,25(OH)2D 3 treatment included reduced glomerular IC deposition, decreased B cell and dendritic cell (DC) infiltration, preservation of proximal tubule brush borders, and decreased glomerular damage. Proximal tubular MHC II upregulation occurred when initiating treatment from 3 weeks of age, and suppression was observed when beginning treatment from 16 weeks of age. In addition, a significant reduction in splenomegaly was observed with 1,25(OH)2D3 treatment. Chronological examination of the effects of 1,25(OH)2D 3 treatment revealed an early retardation of glomerular IC deposition, a decreased B cell infiltration, and a suppression of proximal tubular MHC II expression. A significant increase in renal tubular regeneration was also observed further into treatment.;1,25(OH)2D3 treatment caused significant elevations in serum calcium levels caused stunted growth and kidney calcification. We dosed MRL/lpr mice with various doses of the potent 1,25(OH)2D 3 analog 2-methylene-19-nor-(20S)-1 alpha,25-(OH)2D 3 (2MD) to determine if the analog has specificity for the immune system as it does on bone. We found that 5 ng of 2MD per mouse per day is sufficient to prevent proteinuria while causing only a small increase in serum calcium. Furthermore, 1 ng of 2MD showed over a 60% reduction in proteinuria while maintaining serum calcium levels within physiologically normal range. Only the 5 ng 2MD group, which had the highest serum calcium levels had reduced splenomegaly.;We conclude that (1) 1,25(OH)2D3 and its analog 2MD acts directly on the kidney to prevent LN pathogenesis, and (2) hypercalcemia may have an additive effect in suppressing SLE. Our findings strongly suggest further development of 1,25(OH)2D3 analogs such as 2MD as SLE and LN treatments to reduce the symptoms of LN.