Deleting the TGF-β receptor in proximal tubules impairs HGF signaling

Transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) play key roles in regulating the response to renal injury but are thought to mediate divergent effects on cell behavior. However, how TGF-β signaling alters the response to HGF in epithelia, the key site of HGF signaling in the injured kidney, is not well studied. Contrary to our expectation, we showed that deletion of the TGF-β type II receptor in conditionally immortalized proximal tubule (PT) cells impaired HGF-dependent signaling. This reduced signaling was due to decreased transcription of c-Met, the HGF receptor, and the TGF-β-dependent c-Met transcription and increased response to HGF in PT cells were mediated by the Notch pathway. The interactions of TGF-β, HGF, and Notch pathways had biologically significant effects on branching morphogenesis, cell morphology, migration, and proliferation. In conclusion, epithelial TGF-β signaling promotes HGF signaling in a Notch-dependent pathway. These findings suggest that TGF-β modulates PT responses not only by direct effects, but also by affecting other growth factor signaling pathways.