Transforming growth factor-β1 stimulates hedgehog signaling to promote epithelial–mesenchymal transition after kidney injury

Abstract

The epithelial–mesenchymal transition (EMT) of tubular epithelial cells (TECs) is crucial for the induction and progression of kidney fibrosis. However, the underlying molecular mechanisms that trigger the EMT programme have not been identified. In the present study, we demonstrate that transforming growth factor (TGF)-β1 and activated hedgehog signaling mediate the EMT programme following kidney injury. Tissue samples from fibrotic kidneys show enhanced TGF-β1 levels, as well as upregulated hedgehog signaling activity, during the EMT process; these levels decrease when fibrosis is reversed. Injury promotes TGF-β1 expression and activates hedgehog signaling, thus inducing tubular EMT of TECs and extracellular matrix (ECM) accumulation in vitro. The EMT response and fibrotic appearance are also induced by enhanced TGF-β1 levels or activated hedgehog signaling. Downregulation of TGF-β1 inhibits aristolochic acid (AA)- and TGF-β1-induced EMT and ECM synthesis and correlates with decreased hedgehog signaling. Similarly, inhibiting the hedgehog pathway abolishes AA- and hedgehog-mediated EMT, resulting in reduced TGF-β1 levels. These findings highlight a key role for cross-talk between TGF-β1 and hedgehog signaling in promoting injury-induced EMT and ECM deposition in TECs.