The role of tubular epithelial-mesenchymal transition in progressive kidney disease

The accumulation of interstitial matrix represents the final common pathway of most forms of kidney disease. Much of this matrix is synthesized by interstitial myofibroblasts, recruited from resident fibroblasts and circulating precursors. In addition, a significant proportion is derived from epithelial-mesenchymal transition (EMT) of tubuloepithelial cells. The importance of EMT has been demonstrated in experimental models, where blockade of EMT attenuates renal fibrosis. Although a number of factors may initiate EMT in the kidney, the most potent is transforming growth factor-beta1 (TGF-beta1). Moreover, many other prosclerotic factors have effects on EMT indirectly, via induction of TGF-beta1. Signaling events in this pathway include activation of Smad/integrin-linked kinase (ILK) and connective tissue growth factor (CTGF). Basement membrane integrity is also a key regulator of EMT. In particular, overexpression of matrix metalloproteinase-2 has a key role in the initiation of EMT, membrane dissolution, and the interstitial transit of transformed mesenchymal cells. Endogenous inhibitors of EMT also play an important counterregulatory role both to prevent EMT and stimulate uncommitted cells to regain their tubular phenotype (mesenchymal-epithelial transition). Such inhibitors represent a potential therapeutic approach, offering a mechanism to slow or even redress established renal fibrosis.