Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy

Background. Proteinuria plays a central role in the progression of glomerul ar disease, and there is growing evidence suggesting that it may determine tubular cell activation with release of chemokines and fibrogenic factors, leading to interstitial inflammatory reaction. However, most studies on thi s subject have been performed in experimental models, and the experience in human kidney biopsies has been scarce. We analyzed the tissue sections of patients with idiopathic membranous nephropathy (IMN), a noninflammatory gl omerular disease that may follow a progressive disease with heavy persisten t proteinuria, interstitial cell infiltration, and decline of renal functio n. Methods. Paraffin-embedded biopsy specimens from 25 patients with IMN (13 p rogressive and 12 nonprogressive) were retrospectively studied by immunohis tochemistry [monocyte chemoattractant protein-1 (MCP-1), regulated on activ ation normal T-cell expressed and secreted chemokine (RANTES), osteopontin (OPN), platelet-derived growth factor-BE (PD-GF-BB)] and in situ hybridizat ion [MCP-1, RANTES, PDGF-BB, transforming growth factor-beta 1 (TGF-beta 1) ]. Moreover, we studied the presence of myofibroblasts, which were identifi ed by the expression of alpha-smooth muscle actin (alpha-SMA), the monocyte s/macrophages (CD68-positive cells), and T-cell infiltration (CD4+ and CD8 cells). All of the patients were nephrotic and without treatment at time o f the biopsy. Results. A strong up-regulation of MCP-1, RANTES, and OPN expression was ob served, mainly in tubular epithelial cells, with a significant major intens ity in the progressive IMN patients. A strong correlation between the mRNA expression and the corresponding protein was noted. The presence of these c hemokines and OPN was associated with interstitial cell infiltration. TGF-b eta and PDGF were also up-regulated, mainly in tubular epithelial cells, wi th a stronger expression in the progressive IMN, and an association with th e presence of myofibroblasts was found. Conclusions. Patients with severe proteinuria and progressive IMN have an o verexpression in tubular epithelial cells of the chemokines MCP-1, RANTES, and OPN and the profibrogenic cytokines PDGF-BB and TGF-beta. Because this upregulation was associated with an interstitial accumulation of mononuclea r cells and an increase in myofibroblastic activity, it is suggested that t hose mediators are potential predictors of progression in IMN. Finally, bas ed on experimental data and the findings of this article, we speculate that severe proteinuria is the main factor responsible for the up-regulation of these factors in tubular epithelial cells.