Cytokine, chemokine and growth factor expression in the pathogenesis of progressive renal damage

Chronic renal diseases are untreatable conditions characterized by a final phase of progressive impairment of renal function, leading to end-stage renal failure (ESRF). Once the primary injury has damaged a part of the nephron, the remainder undergo a number of adaptative changes leading to glomerulosclerosis, interstitial fibrosis and, consequently, end-stage kidney disease. Glomerular lesions, mainly represented by mesangial cell proliferation, mononuclear cell infiltration and extracellular matrix deposition, have always been considered as the key factors in the progression of renal damage. However, in this context, it is now clear that the degree of tubulointerstitial damage is a better prognostic marker than the extent of glomerular lesions. Tubulointerstitial involvement is characterized by monocyte and neutrophil infiltration, tubular atrophy, proliferation of interstitial fibroblasts, that acquire a myofibroblast-like phenotype and, finally, extracellular matrix deposition. The pathogenesis of these histological changes is largely unknown, but there is an increasing body of evidence suggesting the possible involvement of some soluble factors produced and released locally, such as cytokines, chemokines and growth factors. Aiming to elucidate the pathogenetic mechanisms underlying glomerular and tubulointerstitial damage in progressive renal diseases, we investigated the renal gene and protein expression of some of these soluble factors. On the basis of the histopathological lesions, we decided to focus our attention on monocyte chemotactic peptide-1 (MCP-1), a specific chemotactic and activating factor for monocytes, on complement C3, a powerful activator of neutrophils, on epidermal growth factor (EGF), the physiological modulator of tubular cell growth, on platelet-derived growth factor (PDGF), the most powerful mitogenic and activating peptide for mesenchymal cells and on transforming growth factor-beta (TGF-beta), the main regulator of extracellular matrix synthesis and degradation.