Aldosterone Blockade and Mineralocorticoid Receptor in CKD
A fact that remains puzzling is the intensifying role of a HS/volume environment for the deleterious effects of aldosterone in the cardiovascular system and the kidney. A 'HS' state facilitates the deleterious effects of MR activation. Seventy years ago, in a seminal study, Hans Selye demonstrated that when he administered deoxycorticosterone acetate to a rodent model with partial renal ablation, a HS intake (3% saline) was required to elicit striking vascular inflammatory changes in the heart and the kidney. Recent studies in the Dahl salt-sensitive rats have suggested that HS diet induces oxidative stress thereby promoting MR activation in the kidney. The implications of these observations are relevant for both an understanding of the pathogenesis of MR–induced renal injury, and a platform for formulating a rational treatment regimen for conferring renal beneficial effects in the CKD patient and diabetic nephropathy.
This formulation is supported by studies demonstrating that aldosterone-induced injury is prevented or ameliorated by dietary sodium restriction suggesting that sodium restriction affects the balance of positive and negative effects induced by aldosterone. Mechanistically, when ingesting a liberal sodium intake, acute aldosterone administration reduces phosphorylated extracellular nitric oxide synthetase (which is vascular protective) and increases phosphorylated extracellular signal-regulated kinases 1 and 2 and protein kinase C (deleterious to the vasculature). In contrast, dietary sodium restriction increases phosphorylated extracellular nitric oxide synthetase and decreases phosphorylated extracellular signal-regulated kinases 1 and 2 and protein kinase C basally, and minimizes or reverses their responses to acute aldosterone administration.
This relationship becomes clinically relevant when patients display plasma aldosterone levels that are inappropriate for the amount of dietary salt consumption or the magnitude of intravascular volume. Patients presenting any degree of volume retention or those consuming a HS diet should demonstrate low levels of circulating aldosterone.
HS ('Inappropriate Salt') State Enhances Renal Injury and Vascular Inflammatory Effects of MR Activation
A fact that remains puzzling is the intensifying role of a HS/volume environment for the deleterious effects of aldosterone in the cardiovascular system and the kidney. A 'HS' state facilitates the deleterious effects of MR activation. Seventy years ago, in a seminal study, Hans Selye demonstrated that when he administered deoxycorticosterone acetate to a rodent model with partial renal ablation, a HS intake (3% saline) was required to elicit striking vascular inflammatory changes in the heart and the kidney. Recent studies in the Dahl salt-sensitive rats have suggested that HS diet induces oxidative stress thereby promoting MR activation in the kidney. The implications of these observations are relevant for both an understanding of the pathogenesis of MR–induced renal injury, and a platform for formulating a rational treatment regimen for conferring renal beneficial effects in the CKD patient and diabetic nephropathy.
This formulation is supported by studies demonstrating that aldosterone-induced injury is prevented or ameliorated by dietary sodium restriction suggesting that sodium restriction affects the balance of positive and negative effects induced by aldosterone. Mechanistically, when ingesting a liberal sodium intake, acute aldosterone administration reduces phosphorylated extracellular nitric oxide synthetase (which is vascular protective) and increases phosphorylated extracellular signal-regulated kinases 1 and 2 and protein kinase C (deleterious to the vasculature). In contrast, dietary sodium restriction increases phosphorylated extracellular nitric oxide synthetase and decreases phosphorylated extracellular signal-regulated kinases 1 and 2 and protein kinase C basally, and minimizes or reverses their responses to acute aldosterone administration.
This relationship becomes clinically relevant when patients display plasma aldosterone levels that are inappropriate for the amount of dietary salt consumption or the magnitude of intravascular volume. Patients presenting any degree of volume retention or those consuming a HS diet should demonstrate low levels of circulating aldosterone.
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