TGF-β Signaling and the Renal Tubular Epithelial Cell

Abstract

TGF-β is the paradigmatic profibrotic cytokine and has also been implicated in epithelial-to-mesenchymal transition (EMT).1,2 TGF-β signaling involves ligand binding to the serine-protein kinase TGF-β receptor II (TβRII), which then recruits another serine-protein kinase, TbRI, and thereby initiates a signaling cascade. In this issue of the JASN , Gewin et al. 3 describe seemingly paradoxic findings: Whereas deletion of TβRII in the murine collecting duct is associated with normal renal development, in ureteral obstruction, there was enhanced rather than the expected diminution of medullary fibrosis. In ureteral obstruction, TβRII null mice manifest more tubular cell flattening (perhaps evidence for EMT), although this was not directly shown, together with more tubular cell loss, more proteinaceous casts, and more interstitial fibrosis associated with collagen I deposition compared with wild-type mice. The authors' search for the responsible mechanisms excluded increased tubular cell apoptosis and increased numbers of inflammatory cells. They demonstrated increased active TGF-β in kidney tissue and used cultured collecting duct cells with deletion of TβRII to demonstrate that increased activation of integrin αvβ6 was responsible for the observed increase in TGF-β activity. Furthermore, they presented evidence that RhoA activates in TβRII null cells, which is relevant because Rho activation associates with activation of integrin αvβ6; suppression of RhoA activity leads to less …