Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity

Abstract

Hyperaldosteronism is associated with impaired vascular reactivity; however, the mechanisms by which aldosterone promotes endothelial dysfunction remain unknown. Glucose-6-phosphate dehydrogenase (G6PD) modulates vascular function by limiting oxidant stress to preserve bioavailable nitric oxide (NO(*)). Here we show that aldosterone (10(-9)-;10(-7) mol/l) decreased endothelial G6PD expression and activity in vitro, resulting in increased oxidant stress and decreased NO(*) levels-similar to what is observed in G6PD-deficient endothelial cells. Aldosterone decreased G6PD expression by increasing expression of the cyclic AMP-response element modulator (CREM) to inhibit cyclic AMP-response element binding protein (CREB)-mediated G6PD transcription. In vivo, infusion of aldosterone decreased vascular G6PD expression and impaired vascular reactivity. These effects were abrogated by spironolactone or vascular gene transfer of G6pd. These findings demonstrate that aldosterone induces a G6PD-deficient phenotype to impair endothelial function; aldosterone antagonism or gene transfer of G6pd improves vascular reactivity by restoring G6PD activity.

Aldosterone Increases Oxidant Stress to Impair Guanylyl Cyclase Activity by Cysteinyl Thiol Oxidation in Vascular Smooth Muscle Cells

“…Dichlorodihydrofluorescein Fluorescence-ROS generation was assessed using 6-carboxy-2Ј,7Ј dichlorodihydrofluorescein diacetate ester fluorescence (5 mol/liter) (Molecular Probes) as described previously (7).…”

“…In the vascular endothelium, aldosterone has been shown to promote endothelial dysfunction by inducing an acquired antioxidant-deficient state that disrupts cellular redox homeostasis to increase ROS accumulation and diminish NO ⅐ levels. In vivo, this results in diminished endothelium-dependent vascular reactivity (7). The relationship between aldosterone-induced oxidant stress and NO ⅐ -stimulated vasodilatory signaling pathways in VSMC, however, remains unknown.…”

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…120 Finally, it has been shown that aldosterone induces a G6PD-deficient phenotype that can be improved by aldosterone antagonist or gene transfer of G6PD. 121 Of great interest, it has recently been suggested that, similar to what has been described in the heart, brain and vasculature, 122 the eye has a dynamic aldosterone-mineralocorticoid receptor system that has an important pathophysiological role in the development of retinal pathology. Wilkinson-Berka et al 123 , using a rat model of oxygen-induced retinopathy (OIR) that has features of premature retinopathy in humans with neovascularization, have shown that mineralocorticoid receptor antagonism with spironolactone improves retinal angiogenesis by attenuating leukostasis and decreasing proinflamatory responses.…”

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

“…A recent report indicates that aldosterone induces a downregulation of endothelial glucose-6-phosphate dehydrogenase that results in impaired oxidative stress and decreased NO availability. Interestingly, these effects of aldosterone were completely prevented by spironolactone (31). In support to this, we have recently shown that spironolactone completely prevented renal acute injury induced by ischemia-reperfusion by a mechanism that involved preservation of renal plasma flow, reestablishment of urinary NO 2 /NO 3 excretion that was accompanied by increased expression of eNOS and phosphorylation at its residue S1177, as well as by a reduction of lipoperoxidation and cell apoptotic death, indicating indeed that aldosterone also participates in hypoperfusion observed in this model (36).…”