Epithelial-mesenchymal transition and fibrosis are mutually exclusive reponses in shear-activated proximal tubular epithelial cells

Renal fibrosis (RF) is thought to be a direct consequence of dedifferentiation of resident epithelial cells via an epithelial-mesenchymal transition (EMT). Increased glomerular flow is a critical initiator of fibrogenesis. Yet, the responses of proximal tubular epithelial cells (PTECs) to fluid flow remain uncharacterized. Here, we investigate the effects of pathological shear stresses on the development of fibrosis in PTECs. Our data reveal that type I collagen accumulation in shear-activated PTECs is accompanied by a similar to 40-60% decrease in cell motility, thus excluding EMT as a relevant pathological process. In contrast, static incubation of PTECs with TGF beta 1 increases cell motility by similar to 50%, and induces stable expression of key mesenchymal markers, including Snail1, N-cadherin, and vimentin. Ectopic expression of TGF beta 1 in shear-activated PTECs fails to induce EMT-associated changes but abrogates collagen accumulation via SMAD2-dependent mechanisms. Shear-mediated inhibition of EMT occurs via cyclic oscillations in both ERK2 activity and downstream expression of EMT genes. A constitutive ERK2 mutant induces stable expression of Snail1, N-cadherin, and vimentin, and increases cell motility in shear-activated PTECs by 250% without concomitant collagen deposition. Collectively, our data reveal that RF not only occurs without EMT but also that these two responses represent mutually exclusive cell fates.-Grabias, B. M., Konstantopoulos, K. Epithelial-mesenchymal transition and fibrosis are mutually exclusive reponses in shear-activated proximal tubular epithelial cells. FASEB J. 26, 4131-4141 (2012). www.fasebj.org