Mechanism of Glomerular Basement Membrane Thickening in Human Membranous Nephropathy / 대한신장학회잡지

Membranous nephropathy is the most common cause of nephrotic syndrome in adult. To investigate the molecular mechanisms which underlie thickening of glomerular basement membrane, we analyzed alpha1(IV) collagen, alpha4(IV) collagen, laminin A, laminin B1, laminin B2, s-laminin, fibronectin, TGF-beta1 and TGF-beta2 mRNA expression in 21 renal biopsies with membranous nephropathy using in situ hybridization. In addition, 7 renal biopsies with no detectable abnormalities were used as control. In membranous nephropathy, the numbers of glomerular visceral epithelial cells expressing alpha1(IV) collagen, alpha4(IV) collagen, s-laminin and TGF-beta1 mRNA were significantly larger than in controls(p<0.05). Laminin A, laminin B1, laminin B2, fibronectin, and TGF-beta2 mRNA were rarely expressed in membranous nephropathy and in control group. The number of TGFbeta-1 mRNA expressing cells/glomerular cross-section correlated to that of alpha1(IV) collagen mRNA expressing cells (p< 0.05). These results indicate that increased presence of glomerular basement membrane proteins in spikes of membranous nephropathy is associated with enhanced mRNA expression of those proteins in the glomerular visceral epithelial cells. Subepithelial deposits in membranous nephropathy stimulate glomerular visceral epithelial cells to produce TGF-beta1, which in turn could mediate the expression of glomerular basement membrane protein genes by glomerular visceral epithelial cells.

Type IV Collagen mRNA Expression in Human Membranous Nephropathy

Human membranous nephropathy (MN) is morphologically characterized by subepithelial immune complex deposits and progressive thickening of glomerular basement membranes (GBM). Studies have suggested that the enhanced secretion of classical and novel type IV collagen chains in MN contributes to spike formation and the novel type IV collagen chain is particularly related to thickening of GBM. It is unclear whether the increased accumulation of extracellular matrix (ECM) proteins in GBM is due to the increased mRNA expression for type IV collagen in glomerular visceral epithelial cells (GECs). To answer this question, we analyzed seven renal biopsies of patients with idiopathic MN using in situ hybridization. In MN, the number of GECs expressing mRNA for alpha1(IV) collagen was 2.82+/-1.80/glomerular cross section (gcs), and the number expressing mRNA for alpha4(IV) collagen was 8.42+/-2.85/gcs. The number of GECs expressing mRNA for alpha4(IV) collagen was significantly larger than that of alpha1(IV) collagen mRNA. The expression of mRNA for these ECM proteins in normal controls was negligible. These results suggest that subepithelial immune complexes stimulate the gene expression of alpha1(IV) collagen and alpha4(IV) collagen in glomerular GECs which, in turn, increase the secretion of ECM proteins and contribute to the thickening of GBM in MN.