Although mTOR inhibitors have been used in clinical routine for more than 20 years, the segment specific renal tubular function of the mTORC1 and mTORC2 complexes have not been explored so far. Using kinase complex specific conditional knock-out animals for Raptor and Rictor, essential scaffolding proteins for mTORC1 and mTORC2 respectively, we could demonstrate a variety of tubular segment specific functions for both kinase complexes. In proximal tubular cells we found that mTORC1 regulates nutrient uptake and endocytosis by influencing either the phosphorylation state or abundance of rate-limiting proteins. In addition mTORC1 determines apoptosis and proliferation after ischemia reperfusion injury a clinically very important problem. In the thick ascending limb we found that mTORC1 via PGC1-α is critical to maintain mitochondrial integrity and activity. Furthermore, mTORC2 is a vital regulator of distal tubular potassium secretion and loss of mTORC2 leads to life threatening hyperkalemia. Finally our studies indicate that both kinase complexes seem to be involved in pathomechanistic processes of several types of renal diseases e.g. polycystic kidney disease, renal fibrosis or diabetic nephropathy.
Furthermore, we focus on the cross-talk of mTOR signaling pathway, autophagy and metabolism using comprehensive proteomics and transcriptomics approaches. In various mouse models of
mTOR hyper- and hypoactivation we perform broad metabolic profiling to gain insights into down-stream effects of this pathway. Our reporter systems allow us to purify ex vivo isolated
podocytes for cell specific profiling. Aim of our research is the identification of new key molecules which might serve as novel drug targets to prevent or treat diabetic
Oliver Kretz, MD