Paracrine role for TGF-ß-induced CTGF and VEGF in mesangial matrix expansion in progressive glomerular disease

Abstract

Transforming growth factor-ß (TGF-ß) is a key regulator of extracellular matrix (ECM), and may mediate the development of glomerulosclerosis with accumulation of mesangial matrix. Mesangial cells secrete TGF-ß in response to common in vitro fibrogenic stimuli. Yet mesangial immunostaining for active TGF-ß1 is frequently negative in chronic glomerular disease. TGF-ß is rather expressed and/or activated by podocytes in both mesangial and podocyte diseases. Activated TGF-ß/Smad signaling by podocytes may induce connective tissue growth factor (CTGF or CCN2) and vascular endothelial growth factor (VEGF) expression. Podocyte CTGF seems to have paracrine effects on mesangial cells to stimulate CTGF expression. CTGF appears to stimulate the fibronectin-matrix assembly via enhanced cell-surface expression of α5ß1 integrin in the mesangium of diseased glomeruli. Podocyte VEGF-A overexpression also seems to play a paracrine role on mesangial cells to upregulate VEGF/VEGF receptor systems and to overproduce matrix proteins. Thus, paracrine CTGF and VEGF may contribute to mesangial matrix accumulation in chronic glomerular disease, culminating in the development of glomerulosclerosis. Together, these data bring new mechanistic insights into our understanding of the pathogenic role of TGF-ß-induced CTGF and VEGF in mesangial matrix expansion in chronic progressive glomerular disease