Contribution of AMPK via Rheb/mTORC1 for the renal fibrosis mechanism

Abstract

In the last decade, chronic kidney disease (CKD) affected approximately 10% of the world population. The DRC, regardless of the cause, is accompanied by a process of progressive fibrosis of the renal parenchyma and generates an accumulation of extracellular matrix. Myofibroblasts are cells responsible for tissue repair, and are positively regulated by other molecules, especially TGF-², which is the main factor related to renal fibrogenesis. AMPK kinase is a serine/threonine kinase that regulates the cellular energy homeostasis and its activation is reduced in gluconeogenesis and fatty acid synthesis Futhermore, many publications show reduced activation of AMPK in fibrosis. It has also recently been suggested that Rheb/mTORC1 signaling could activate kidney myofibroblasts after inducing fibrosis and that ths contributes to the development of interstitial fibrosis. Abnormal activation of mTORC1 is involved in the pathogenesis of podocyte dysfunction and renal fibrosis. Since it is known that TGF-², a potent inducer of epithelial-mesenchymal transformation and renal fibrosis, promotes at the same time: inactivation of AMPK and activation of mTORC1 through Rheb/TSC1/TSC2. However, if the inactivation of AMPK contributes to the activation of mTORC1 through Rheb/TSC1/TSC2 in fibrosis remains to be investigated. The aim of this study is to test whether activation of the Rheb/TSC1/TSC2 is AMPK-dependent in fibroblasts exposed to TGF -². (AU)