Extracellular matrix deposition and cell proliferation in a model of chronic glomerulonephritis in the rat

Background. Resident glomerular cell proliferation, matrix deposition and s ecretion of matrix metalloproteinases play a major role in the progression of chronic glomerular disease. These features were studied in a novel appro ach in a rat model of chronic glomerulonephritis induced by four injections of an anti-Thy 1.1 antiserum at weekly intervals. Methods. Chronic immune mediated mesangial injury was induced in male Sprag ue-Dawley rats by repeated intravenous injection of an anti-Thy 1.1 antiser um. One week after the first and fourth injection of the antiserum proteinu ria was evaluated and the kidneys were removed. Immunohistology was perform ed for proliferating cells, monocytes and collagen type IV. Furthermore, mR NA expression of collagen type IV, TGF-beta and the matrix degrading enzyme MMP-2 as well as MMP-2 protein expression were studied. Results. Urinary protein excretion was dramatically increased after one ant iserum injection and stayed elevated at a lower level after the fourth anti serum injection. After the initial induction of nephritis, 7 days following antiserum, resident glomerular cell proliferation was increased whereas wi th repeated injections of the antiserum cell numbers were not different fro m controls, as measured 1 week after the fourth injection. In contrast, ext racellular matrix accumulation (collagen type IV) increased after the first antiserum injection and further increased after the fourth antiserum injec tion. The mRNA expression for collagen type IV increased after the first an tiserum injection and showed further increase after the fourth antiserum in jection. Induction of nephritis also stimulated glomerular mRNA expression of MMP-2 and TGF-beta, both of which remained at a high level after the fou rth antiserum injection. Glomerular protein levels of MMP-2 also increased after the first antiserum injection and showed a further slight increase af ter the fourth injection. Conclusion. Increased cellular proliferation is involved in an early stage of this disease, while enhanced expression of glomerular matrix and augment ed mRNA and protein expression of the matrix degrading enzyme MMP-2 continu e into the chronic phase, and contribute to the extensive structural remode ling process that accompanies this form of glomerular injury.