Investigation of mTOR regulated metabolic processes in podocytes

Abstract

Diabetic nephropathy (DN) is one the main causes of kidney chronic disease that leads the patients to the end stage renal disease. One of the hallmark of DN is the damage to the glomerular filtration barrier (GFB) which triggers proteinuria. The damages to GFB are linked to loss and deregulation of podocytes, the main component involved on the selectivity and glomerular homeostasis. Podocytes exposed to high glucose levels, as found during DN, change its metabolic state and the way to obtain energy. The maintenance of cell functions demands high energy production while bioenergy changes trigger signaling pathways that drive important cellular processes. The literature describes that alteration on ATP and AMP generation modulates, through AMPK, the levels of mTOR activity. The mTOR complexes are kinases associated to a wide range of biologic processes, among them the protein synthesis and podocyte homeostasis. However, the events that link mTOR activation depending energy variation and protein synthesis to keep podocyte homeostasis are not well understood. In this project we intend to study the hypothesis that the energy regulation system, through mTOR/AMPK, is associated to protein synthesis regulation which is important to podocyte and GFB function. To do that, we will isolate podocytes from Raptor/Rictor/AMPK-deficient mice and will analyze the role of these proteins on podocyte bioenergy variation as well as cytoskeleton organization when exposed to high glucose levels. We hope that the results evidence somehow the involvement of mTORC1 and mTORC2 on the regulation of metabolic variation and the maintenance of podocyte architecture on DN.