Abstract
Chronic kidney disease is characterized by markedly increased risk for cardiovascular mortality, vascular calcification, and ventricular hypertrophy, and is associated with increased systemic oxidative stress. Hyperphosphatemia, reflecting diminished glomerular phosphate (Pi) clearance, coupled with a compensatory increase in fibroblast growth factor 23 (FGF23) secretion are thought to be key mediators of this risk. Elevated serum and dietary Pi and elevated plasma FGF23 are associated with increased cardiovascular and total mortality in people with normal baseline renal function. FGF23 may mediate some of this risk by promoting cardiac hypertrophy via activation of fibroblast growth factor receptor 4 on cardiomyocytes. Elevated serum Pi can also cause a profound increase in systemic oxidative stress, and this may reflect the ability of Pi to act directly on mitochondria to boost membrane potential and thereby increase respiratory chain superoxide production. Moreover, elevated FGF23 likewise induces oxidative stress in vascular endothelium via activation of NADPH oxidase complexes. In vitro exposure of vascular smooth muscle cells to elevated Pi provokes an osteoblastic phenotypic transition that is mediated by increased mitochondrial oxidant production; this is offset dose-dependently by increased exposure to magnesium (Mg). In vivo, dietary Mg is protective in rodent models of vascular calcification. It is proposed that increased intracellular Mg opposes Pi’s ability to increase mitochondrial membrane potential; this model could explain its utility for prevention of vascular calcification and predicts that Mg may have a more global protective impact with regard to the direct pathogenic effects of hyperphosphatemia.
Highlights
Mitochondrial diseases are a group of conditions in which mitochondrial dysfunction leads to cellular failure to generate sufficient ATP to maintain cellular homeostasis, and/or mitochondrial oxidant generation adversely affects the function or survival of cells [1]
While dietary phosphate (Pi) is self- essential for health, chronically elevated Pi levels associated with impaired glomerular function and episodic elevations reflecting diets rich in bioavailable Pi—from animal products and Pi food additives—are associated with increased cardiovascular risk characterized by vascular calcification [7,8]
The thesis presented here is that improved Mg status can function as a detoxicant for Pi excess by opposing the tendency of elevated Pi to promote excess oxidant production by mitochondria
Summary
Mitochondrial diseases are a group of conditions in which mitochondrial dysfunction leads to cellular failure to generate sufficient ATP to maintain cellular homeostasis, and/or mitochondrial oxidant generation adversely affects the function or survival of cells [1]. A common dominator in these chronic conditions is oxidative stress and vascular dysfunction, as seen in cardiovascular [5] and renal diseases [6]. While dietary phosphate (Pi) is self- essential for health, chronically elevated Pi levels associated with impaired glomerular function and episodic elevations reflecting diets rich in bioavailable Pi—from animal products and Pi food additives—are associated with increased cardiovascular risk characterized by vascular calcification [7,8]. Increased dietary intakes or serum levels of magnesium (Mg) have been correlated with reduced risk of cardiovascular events and vascular calcification [9,10,11]. This oxidative stress promotes a phenotypic transition giving rise to vascular calcification; in vascular endothelium, it can compromise the cardiovascular protection conferred by a healthy endothelium
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