Role of the extracellular matrix in the development of glomerulosclerosis in experimental chronic serum sickness

Glomerulosclerosis is a severe complication of many immunologically mediated kidney diseases and is associated with a poor prognosis with respect to renal function. The aim of this study was to elucidate the role of the extracellular matrix (ECM) in the development of glomerulosclerosis in experimental immune complex glomerulonephritis. Induction of chronic serum sickness by repetitive injections of human IgG into preimmunized Wistar rats leads to the development of immune complex nephritis and glomerulosclerosis. At an early stage of the disease fibrinogen accumulation was observed along the endothelial cells, presumably related to damage of the endothelial lining. mRNA levels for several collagen types, laminin B1 and B2, and fibronectin were increased in both whole-kidney tissue and in isolated glomeruli, but morphological changes were not observed. In situ hybridization experiments demonstrated increased ECM mRNA levels in glomerular and tubular cells. Starting at week 15, glomerular mesangial matrix expansion and thickening of the glomerular basement membrane (GBM) was observed. ECM components were abundantly present. Coagulation factors were not observed at this point. ECM mRNA levels were decreased as compared to week 0, but were still above normal. Focal and segmental end-stage sclerotic lesions developed at weeks 25-30, in which fibronectin and fibrinogen were the major constituents. Other ECM components were found peripherally from these lesions in the remnants of the mesangial matrix and GBM. Sclerotic matrices did not demonstrate an increase of cellular-fibronectin, and other constituents from the circulation were not present in the lesions. Glomerular ECM mRNA was decreased to normal levels. However, a dramatic increase of ECM mRNA expression was observed at sites of inflammatory infiltrate in the perivascular, interstitial, and periglomerular regions. In conclusion, the development of glomerulosclerosis in chronic serum sickness rats is preceded by mesangial matrix expansion in which several ECM components are increasingly expressed. Steady state mRNA levels for these components are increased before morphological changes are detectable. In the final stage there is a specific accumulation of exogenous fibronectin in the glomerular end-stage sclerotic lesions. Simultaneously, an interstitial inflammatory reaction takes place leading to increased ECM production in the tissue surrounding the damaged glomeruli.