Effects of 1,25(OH)(2)D-3 in experimental mesangial proliferative nephritis in rats

Background. 1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3], the active form of vitamin D,, is a potent immunomodulatory agent on several cell types such as monocytes and mesangial cells. Recruitment of inflammatory cells, as well as stimulation of resident cells and mesangial matrix accumulation are key features of various experimental and human glomerular diseases. Here we show that 1,25(OH)(2)D-3 attenuates the morphologic and functional alterations in anti-Thy-1,1. nephritis. an experimental model of mesangial proliferative glomerulonephritis. Methods. The anti-Thy-1,1 group (group I) comprised 24 rats that at day 0 received 0.5 mt of saline containing 400 mug of monoclonal antibodies (mAb) anti-Thy-1,1 IgG. The antiThy-1,1 treated with 1.25(OH)(2)D-3 group (group II) were 24 rats given 1,25(OH)(2)D-3 at the dose of 25 ng/100 g body wt/day. From day -3 to day 14. At day 0, the rats received 400 mug of anti-Thy-1,1 monoclonal IgG. The control group (group III) comprised 12 rats injected with vehicle alone; the control group treated with 1,25(OH)(2)D-3 (group IV)-12 rats were given 1,25(OH)(2)D-3 as in group II without mAb administration. Proteinuria and urinary interleukin-h excretion were measured daily. Blood urea nitrogen and creatinine, creatinine clearance. calcium, and phosphate were measured at days 0, 4, 7, and 14. In addition to conventional periodic acid-Schiff staining. binding of anti-Thy-1,1 IgG and C3b complement fraction. His48- and ED1-positive cells were studied by immunofluorescence. Mesangial proliferation was studied by the proliferating cell nuclear antigen (PCNA) technique. Apoptosis was evaluated by the TUNEL assay. Results. The anti-Thy-1,1 treated with 1.25(OH),D, group versus the anti-Thy-1,1 alone group showed a significant reduction in urinary protein (at day 7, 424 +/- 228 vs. 66 +/- 30 mg/mg urinary creatinine. P = 0.02) and interleukin-h excretion (at day 3, 537 +/- 360 pg/mL vs. 110 +/- 34 pg/mg urinary creatinine. P = 0.015), reduced glomerular diameters (at day 7. 283 +/- 38 vs. 261 +/- 48 mum. P < 0.01). decreased neutrophil (at day 4, 20 +/- 12 His48-positive cells/glomerulus vs. 3.7 +/- 1.3 His48-positive cells/glomerulus, P < 0.001). and monocyte accumulation (day 7, 4.9 +/- 2.9 ED1-positive cells/glomerulus vs. 2.8 +/- 2.9 ED1-positive cells/glomerulus, P < 0.05), and attenuated glomerular cells proliferation (day 7. 13 +/- 3.2 PCNA-positive cells/glomerulus vs. 9.4 +/- 3 PCNA-positive cells/glomerulus, P < 0.01). Apoptosis showed a biphasic behavior with an early peak at day 4 in the anti-Thy-1,1 group (2.3 +/- 2.2 TUNEL positive ceils/glom) related to cellular lysis and a late peak at day 14 related to the recovery phase. Conclusions. 1,25(OH)(2)D-3 can reduce glomerular hypercellularity, inflammatory infiltration in anti-Thy-1,1 nephritis, preserving the apoptotic response of the reparative phase