Endothelial cell dysfunction (ECD) is the harbinger of majority of cardiovascular disease and is especially prevalent in patients with chronic kidney disease (CKD). During the past 2 cycles of this study we obtained and verified genetic and proteomic signatures of ECD. In the process we established a model of pre-clinical "early" ECD using chronically non-pressor doses of L-NMMA. Renal microvasculature of these mice revealed depletion of 2 key mitochondrial enzymes - enoyl- CoA-hydratase-1 (ECHS-1) and aconitase-2 (Aco-2). Consequently, TCA cycle was inhibited, mitochondrial biogenesis suppressed, and normoxic glycolysis prevailed resulting in the increase of lactate production - a metabolic profile which is a hallmark of Warburg effect. Present application is based on a hypothesis that this metabolic profile of ECD may explain some abnormalities in the pathways of mitochondrial and cytosolic glucose-lipid metabolism. A therapeutic corollary of these findings predicts the possibility of correcting "truncated" TCA cycle by introducing an intermediate bypassing the enzymatic block potentially resulting in alleviation of ECD. Another major goal consists in obtaining the metabolic signatures of advanced ECD accompanied by hypoxic glycolysis (Pasteur effect). We hypothesize that it is responsible for the induction of HIFs, VEGF, and an increase in vascular permeability.
Four Specific Aims are proposed: 1) profiling glucose metabolism of dysfunctional endothelium: links to redox, lipid metabolism, and glyceroneogenesis;2) metabolic consequences of Pasteur effect (hypoxic glycolysis) in advanced ECD: induction of HIFs, VEGF and increased vascular permeability;3) glutamine bypasses mitochondrial enzymatic blockade in endothelial dysfunction: metabolic and functional consequences;culminating in 4) a proof of principal clinical trial of glutamine supplementation in patients with CKD 3-4. Results of these investigations should offer a detailed picture of metabolic disturbances associated with ECD in vitro and in vivo, have a potential to disclose a mechanistically rational therapeutic intervention to restore metabolism and alleviate manifestations of ECD, and finally test these findings on glutamine supplementation and vascular functions in a pilot clinical trial of a select patient population with CKD 3-4.
Studies proposed in this grant application should shed light on two concepts: 1) incompetence of stem/progenitor cells in Chronic Kidney Disease (CKD) contributes to the insufficient regenerative processes thus accounting in part for progression of disease and 2) stem cell incompetence is reversible and can be pharmacologically corrected thus resulting in reduction of the rate of progression or even regression of disease. Among the potential causes of stem cell incompetence in CKD we shall focus on a) stem cell-related factors and b) stem cell niche-related factors, as well as attempt pharmacologic correction of stem cell incompetence. These studies should supplement the search for mechanisms of progression of CKD by exploring the regenerative potential and its failure in these morbid states and offering alternative therapeutic strategies.
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