Figure 4

Schematic illustration of the key events of epithelial-mesenchymal transition (EMT) involving the renal tubular basement membrane (TBM) and possible therapeutic interventions. The diagram illustrates four key events essential for the completion of EMT: loss of epithelial adhesion properties; de novo alpha smooth muscle actin (αSMA) expression and actin reorganization; disruption of TBM; and enhanced cell migration and invasion capacity. Transforming growth factor (TGF)-1 alone is capable of inducing tubular epithelial cells to undergo all four steps. Strategies to block any steps during EMT would have a major impact on EMT and, thereby, on renal fibrosis. For instance, hepatocyte growth factor (HGF) and bone morphogenic protein (BMP)-7 could antagonize TGF-1 and consequently inhibit the initiation of EMT (step 1). Blockade of angiotensin (Ang)II by losartan abolishes its activity as an EMT promoter and attenuates renal fibrosis (step 2). Preservation of TBM integrity in tPA-/- mice selectively blocked EMT in obstructive nephropathy (step 3). Finally, pharmacological inhibition of ROCK kinase impairs cell migration and reduces renal fibrosis (step 4). MMP, matrix metalloproteinase. (Adapted from [35].)