EMT and proteinuria as progression factors

Tubulointerstitial fibrosis is an integral part of the structural changes of the kidney in chronic progressive renal failure. The accumulation of the extracellular matrix in the tubulointerstitial space is mediated mainly by myofibroblasts. These are derived from resident interstitial fibroblasts, tubular epithelial cells, periadventitial cells, and possibly also mesenchymal stem cells and endothelial cells. Fibrosis is usually preceded by tubulointerstitial infiltration of mononuclear inflammatory cells. Proteinuria is one of several mechanisms of primary glomerular or vascular disease to transmit the disease process to the interstitial space. Increased protein filtration may have direct toxic effects on tubular epithelial cells, induce chemokine and cytokine secretion and result in increased expression of adhesion molecules, all contributing to the influx of mononuclear cells. Inflammatory cells in return secrete cytokines, which stimulate resident fibroblasts and tubular epithelial cells to differentiate into matrix-producing cells. The phenotypic conversion of primary epithelial cells into mesenchymal cells, termed epithelial-mesenchymal transition (EMT), has been studied in great detail in recent years. Several signal transduction pathways of this process have been clarified and may eventually result in novel therapeutic approaches. The severity of proteinuria and the extent of EMT have both been associated with the decline in renal function in clinical studies. Limiting proteinuria results in a slower decline of renal function deterioration, whereas reducing EMT has had beneficial effects in a number of animal studies, including those indicating reversal of fibrotic lesions. However, the association between proteinuria and EMT and vice versa is far from clear and has not been carefully studied