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Snail1-induced partial EMT drives renal fibrosis and supports targeted therapies

Snail1-induces partial epitelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease.

Nature Medicine. Aug 3 , 2015.

M. T. Grande, B. Sánchez-Laorden, C. López-Blau, C. A. de Frutos, A. Boutet, M. Arévalo, R. Grant Rowe, S. J. Weiss, J. M. López-Novoa y M. A. Nieto

Progressive kidney fibrosis contributes greatly to end-stage renal failure, and no specific treatment is available to preserve organ function. During renal fibrosis, myofibroblasts accumulate in the interstitium of the kidney, leading to massive deposition of extracellular matrix and organ dysfunction. The origin of myofibroblasts is manifold, but the contribution of an epithelial-to-mesenchymal transition (EMT) undergone by renal epithelial cells during kidney fibrosis is still debated. We show that the reactivation of Snail1 in mouse renal epithelial cells is required for the development of fibrosis in the kidney. Damage-mediated Snail1 reactivation induces a partial EMT in tubular epithelial cells that impairs renal function, and importantly, without directly contributing to the myofibroblast population, relays signals to the interstitium to promote myofibroblast differentiation, fibrogenesis and to sustain inflammation. We also show that Snail1-induced fibrosis can be reversed in vivo and that obstructive nephropathy can be therapeutically ameliorated in mice by targeting Snail1 expression. These results reconcile conflicting data on the role of the EMT in renal fibrosis and provide avenues for the design of novel anti-fibrotic therapies.

 

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