Lefty A attenuates the TGF-beta1-induced epithelial to mesenchymal transition of human renal proximal epithelial tubular cells.

The epithelial to mesenchymal transition (EMT) is a crucial event for renal fibrosis that can be elicited by TGF-beta1/Smads signaling and its downstream mediator connective tissue growth factor (CTGF). As a distinct member of the TGF-beta superfamily, Lefty A has been shown to be significantly downregulated in the kidneys of patients with severe ureteral obstruction, suggesting its role in renal fibrosis induced by obstructive nephropathy. In order to determine whether Lefty A prevents TGF-beta1-induced EMT, human proximal tubule epithelial cells (HK-2) were stably transfected with Lefty A or control vectors and stimulated with 10 ng/ml TGF-beta1 for 48 h. The results show that stimulation with TGF-beta1 led to EMT including cell morphology changes, Smad2/3 signaling pathway activation, increased alpha-SMA, collagen type I, and CTGF expression, and decreased E-cadherin expression in mock-transfected HK-2 cells. Overexpression of Lefty A efficiently blocked p-Smad2/3 activation and attenuated all these EMT changes induced by TGF-beta1. This finding suggests that Lefty A may serve as a potential new therapeutic target to inhibit or even reverse EMT during the process of renal fibrosis.