Background: Resident glomerular cell proliferation, matrix deposition and secretion of matrix metalloproteinases play a major role in the progression of chronic glomerular disease. These features were studied in a novel approach 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 Sprague-Dawley rats by repeated intravenous injection of an anti-Thy 1.1 antiserum. One week after the first and fourth injection of the antiserum proteinuria was evaluated and the kidneys were removed. Immunohistology was performed for proliferating cells, monocytes and collagen type IV. Furthermore, mRNA 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 antiserum injection and stayed elevated at a lower level after the fourth antiserum injection. After the initial induction of nephritis, 7 days following antiserum, resident glomerular cell proliferation was increased whereas with repeated injections of the antiserum cell numbers were not different from controls, as measured 1 week after the fourth injection. In contrast, extracellular matrix accumulation (collagen type IV) increased after the first antiserum injection and further increased after the fourth antiserum injection. The mRNA expression for collagen type IV increased after the first antiserum injection and showed further increase after the fourth antiserum injection. Induction of nephritis also stimulated glomerular mRNA expression of MMP-2 and TGF-beta, both of which remained at a high level after the fourth antiserum injection. Glomerular protein levels of MMP-2 also increased after the first antiserum injection and showed a further slight increase after the fourth injection.
Conclusion: Increased cellular proliferation is involved in an early stage of this disease, while enhanced expression of glomerular matrix and augmented mRNA and protein expression of the matrix degrading enzyme MMP-2 continue into the chronic phase, and contribute to the extensive structural remodeling process that accompanies this form of glomerular injury.