The scientific premise of this project is based upon the significance of salt-sensitive hypertension as a health problem and the need to understand the underlying mechanisms to enable development of more effective treatments. The studies proposed pursue mTOR signaling, which has long been known to be important in the regulation of cell cycle events and in human cancers, but has remained unexplored in hypertension. It is also recognized that mTOR complexes can participate in autoimmune responses and cardiovascular diseases and studies find they are important for renal podocyte homeostasis and tubular epithelial Na+ and K+ transport. Despite evidence that many aspects of kidney physiology known to be altered in hypertension are negatively affected by stimulation of mTOR complexes, the therapeutic benefit of inhibition of these pathways has not been studied. Indeed, remarkably little is known about the contributions of mTOR to the pathophysiology of hypertension. Our preliminary studies find that inhibition of the mTOR complexes virtually abolished salt-induced hypertension in a rat model of salt-sensitive hypertension (Dahl SS rats). Given that a high salt diet stimulates H2O2 production in the kidney of SS rats, and based on our in vitro evidence, we hypothesize that in the SS rat model of salt-sensitive hypertension enhanced intrarenal production of H2O2, largely from Nox4, enhances mTOR signaling. We propose that activated mTORC2 phosphorylates and activates SGK1; thereby increasing tubular Na+ reabsorption which results in Na+ retention and hypertension (and as studied in Project 3, enhanced inflammation). Project 1 has three Specific Aims:
Aim 1 will test the hypothesis that therapeutic suppression of the mTORC2 pathway will reduce blood pressure salt-sensitivity and renal injury in SS rats.
Aim 2 will test the hypothesis that mTORC2/SGK1 contributes to enhanced tubular Na+ reabsorption and salt-sensitivity of SS rats.
Aim 3 will test the hypothesis that elevations of intrarenal H2O2 in SS rats fed a high salt diet contribute importantly to the activation of the mTOR signaling pathway. These mechanisms are not just of academic interest since understanding of these pathways could yield novel therapeutic targets.
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