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 for mation in immune-mediated glomerular disease, rats with anti-thymocyte antibody-induced glomerulonephritis were treated with prostaglandin E 1 (PGE(1)) (250 mu g/twice daily/s.c.). Glomerular expression of colla gen types III and IV was assessed by Northern blotting, immunohistolog y and Western blot ting. Proliferation of glomerular cells was evaluat ed by staining for the proliferating cell nuclear antigen (PCNA)and co nsecutive cell counting. At day five after induction of the disease, g lomerular mRNA levels of collagen types III and IV were three- to five fold 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 concentrat ion and the deposition of extracellular collagens. The number of PCNA positive cells which was significantly higher in nephritic rats when c ompared with control animals (24 hr, nephritis 2.53 +/- 0.33 and Contr ol 0.26 +/- 0.06, P = 0.011; 5 days, nephritis 5.10 +/- 1.13 and Contr ol 0.75 +/- 0.08, cells per glomerular cross section, P = 0.03) was re duced 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 sect ion, P = 0.001). Prostaglandin E(1) also ameliorated the glomerular in filtration of monocytes at 24 hours (nephritis 4.36 +/- 2.82, nephriti s + 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, cell s per glomerular cross section). To further characterize possible mech anisms by which PGE(1) reduces extracellular matrix deposition, the gl omerular expression of transforming growth factor (TGF-beta), and inte rleukin 1 beta (IL-1 beta) was assessed by Northern blotting. Nephriti c 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 exp ression of extracellular matrix proteins in anti-thymocyte antibody-in duced glomerulonephritis, suggesting a beneficial role of prostaglandi ns in this proliferative glomerular immune injury. The effects of PGE( 1) might be mediated by inhibition of TGF-beta and IL-1 beta productio n.