Prostaglandin E1 inhibits collagen expression in anti-thymocyte antibody-induced glomerulonephritis: Possible role of TGF beta

To test whether or not prostaglandins mediate extracellular matrix formation in immune-mediated glomerular disease, rats with anti-thymocyte antibody-induced glomerulonephritis were treated with prostaglandin E1 (PGE(1)) (250 mu g/twice daily/s.c.). Glomerular expression of collagen types III and IV was assessed by Northern blotting, immunohistology and Western blot ting. Proliferation of glomerular cells was evaluated by staining for the proliferating cell nuclear antigen (PCNA)and consecutive cell counting. At day five after induction of the disease, glomerular mRNA levels of collagen types III and IV were three- to fivefold higher compared with non-nephritic controls. Similarly glomerular deposition of these collagens was markedly increased when assessed by immunohistology. The treatment of nephritic rats with PGE(1) reduced the increased glomerular mRNA levels as well as the protein concentration and the deposition of extracellular collagens. The number of PCNA positive cells which was significantly higher in nephritic rats when compared with control animals (24 hr, nephritis 2.53 +/- 0.33 and Control 0.26 +/- 0.06, P = 0.011; 5 days, nephritis 5.10 +/- 1.13 and Control 0.75 +/- 0.08, cells per glomerular cross section, P = 0.03) was reduced by PGE(1) (24 hr, nephritis + PGE(1) 0.44 +/- 0.30, P = 0.0001; 5 days, nephritis+PGE(1) 1.91 +/- 1.84 cells per glomerular cross section, P = 0.001). Prostaglandin E(1) also ameliorated the glomerular infiltration of monocytes at 24 hours (nephritis 4.36 +/- 2.82, nephritis + PGE(1) 2.20 +/- 1.82, cells per glomerular cross section) and five days (nephritis 1.51 +/- 0.58, nephritis + PGE(1) 1.12 +/- 0.61, cells per glomerular cross section). To further characterize possible mechanisms by which PGE(1) reduces extracellular matrix deposition, the glomerular expression of transforming growth factor (TGF-beta), and interleukin 1 beta (IL-1 beta) was assessed by Northern blotting. Nephritic glomeruli showed increased mRNA levels of TGF-beta at day 5 and IL-1 beta at 24 hours when compared with control kidneys. Treatment of the animals with. PGE(1) inhibited the mRNA expression of TGF-beta and IL-1 beta. These data demonstrate that PGE(1) reduces the glomerular expression of extracellular matrix proteins in anti-thymocyte antibody-induced glomerulonephritis, suggesting a beneficial role of prostaglandins in this proliferative glomerular immune injury. The effects of PGE(1) might be mediated by inhibition of TGF-beta and IL-1 beta production.