Angiotensina II y Gremlin activan la vía Smad durante la transición epitelio-mesenquinal, un mecanismo básico de progresión de daño renal

Resumen

_________ __ Summary Epithelial-mesenchymal transition (EMT) is an important process that contributes to renal fibrosis. Among the factors involved in the progression of renal damage, Angiotensin II (AngII) highlights as inducer of fibrosis. Drugs that block AngII actions are one of the best treatments to slow the progression of kidney diseases. The aim of this thesis was to investigate the molecular mechanisms and mediators involved in EMT. For this purpose, different approaches were done: in vitro, in vivo and in biopsies studies, using various techniques of molecular biology and biochemistry. The results presented in this study show that AngII induces EMT in the kidney through direct activation of the Smad pathway, independently of TGF-ß. The regulation of this process is complex and involves the activation of other intracellular signaling systems (such as MAPK and RhoA/ROCK), and endogenous synthesis of profibrotic mediators such as TGF-ß and CTGF. Taken together, these data show that inhibition of Smad pathway and endogenous synthesis of CTGF could be good therapeutic strategies against renal fibrosis. In addition, these findings explain the renoprotective effect of drugs that block AngII by acting at the cellular level. The study of biopsies from patients with several progressive glomerulopathies showed over-expression of Gremlin in areas of tubulointerstitial fibrosis in co-localization with TGF-ß, Smad activation and EMT markers. Gremlin is regulated in the kidney by key factors in renal damage, such as AngII and TGF-ß. Our in vitro studies demonstrated that Gremlin induces typical changes of EMT through activation of TGF-ß/Smad pathway. These data suggest that Gremlin can be considered as a new mediator of fibrosis. These results extend the knowledge about the molecular processes involved in renal fibrosis and suggest new therapeutic targets for chronic kidney disease.