Aldosterone Blockade and Mineralocorticoid Receptor in CKD
As detailed by John Funder in a recent review, a reasonable summary of the prevailing view of aldosterone and the MR in 1990 posited that: (a) angiotensin was the major determinant of aldosterone secretion, (b) aldosterone is the physiologic ligand for MR, (c) that aldosterone elevates BP by its sodium-retaining effects with consequent volume expansion, (d) MRAs act by blocking the binding of aldosterone to MR, and (e) aldosterone acts genomically and nongenomically.
After 20 years, we realize that the majority of these concepts are wrong. It is now accepted that: (a) angiotensin does not constitute the major driver of aldosterone secretion, (b) aldosterone is merely one of the physiological ligands for MR, (c) although aldosterone's sodium-retaining effects are relevant in defending volume homeostasis in the setting of hypovolemia, aldosterone raises BP primarily by actions on the vasculature and central nervous system. An understanding of this new paradigm for aldosterone constitutes a rational framework for examining the therapeutic potential of MRA in hypertension, CKD, and ESRD.
An understanding of the interaction between aldosterone and the MR is necessary to fully comprehend the new paradigm. The MR is order of magnitude more sensitive to cortisol than to aldosterone. This paradox has been clarified in part by the demonstration by Funder and Myles that the action of 11-beta-hydroxysteroid dehydrogenase-2 was to debulk intracellular glucocorticoid levels, reducing them from 100- to 10-fold those of aldosterone, but not that of metabolizing glucoocorticoids out of existence. Consequently, most epithelial MRs are thus occupied by the approximately 10-fold preponderance of cortisol over aldosterone, but are not activated. The mechanism whereby cortisol-occupied MR remains inactive remains to be defined. Recent studies by Schiffrin have delineated the mechanisms underlying crosstalk between Ang II type 1 receptor and MR. They have demonstrated that the nongenomic and genomic effects of aldosterone are differentially dependent on activity of both Ang II type 1a receptor and Ang II type 1b receptor, thereby providing a mechanistic understanding for the benefit of combination therapy with dual blockade of Ang II type 1 receptor and MR to treat hypertension and progression of heart and kidney failure.
Expansion of the classical concept to the new paradigm is characterized by several additional features that subtend aldosterone's role in promoting target organ damage. First in the presence of high-salt (HS) intake, aldosterone produces persistent hypertension with consequent BP-dependent target organ damage. Second, in a permissive milieu with attendant high-sodium intake, even normal concentrations of aldosterone produce BP–independent target organ damage acting through inflammatory and pro-fibrotic pathways.
Emerging evidence also supports a paradigm shift in our understanding of aldosterone's ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and dysglycemia. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling, which in turn leads to insulin resistance. Indeed, hyperaldosteronism is associated with impaired pancreatic β-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance.
Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the MR. Although we have known that MR blockade attenuates cardiovascular and renal injury, only recently have we learned that MR blockade improves pancreatic insulin release, and insulin-mediated glucose utilization.
How the Aldosterone Paradigm has Changed Markedly: A Platform for Formulating Rational Therapeutics
As detailed by John Funder in a recent review, a reasonable summary of the prevailing view of aldosterone and the MR in 1990 posited that: (a) angiotensin was the major determinant of aldosterone secretion, (b) aldosterone is the physiologic ligand for MR, (c) that aldosterone elevates BP by its sodium-retaining effects with consequent volume expansion, (d) MRAs act by blocking the binding of aldosterone to MR, and (e) aldosterone acts genomically and nongenomically.
After 20 years, we realize that the majority of these concepts are wrong. It is now accepted that: (a) angiotensin does not constitute the major driver of aldosterone secretion, (b) aldosterone is merely one of the physiological ligands for MR, (c) although aldosterone's sodium-retaining effects are relevant in defending volume homeostasis in the setting of hypovolemia, aldosterone raises BP primarily by actions on the vasculature and central nervous system. An understanding of this new paradigm for aldosterone constitutes a rational framework for examining the therapeutic potential of MRA in hypertension, CKD, and ESRD.
An understanding of the interaction between aldosterone and the MR is necessary to fully comprehend the new paradigm. The MR is order of magnitude more sensitive to cortisol than to aldosterone. This paradox has been clarified in part by the demonstration by Funder and Myles that the action of 11-beta-hydroxysteroid dehydrogenase-2 was to debulk intracellular glucocorticoid levels, reducing them from 100- to 10-fold those of aldosterone, but not that of metabolizing glucoocorticoids out of existence. Consequently, most epithelial MRs are thus occupied by the approximately 10-fold preponderance of cortisol over aldosterone, but are not activated. The mechanism whereby cortisol-occupied MR remains inactive remains to be defined. Recent studies by Schiffrin have delineated the mechanisms underlying crosstalk between Ang II type 1 receptor and MR. They have demonstrated that the nongenomic and genomic effects of aldosterone are differentially dependent on activity of both Ang II type 1a receptor and Ang II type 1b receptor, thereby providing a mechanistic understanding for the benefit of combination therapy with dual blockade of Ang II type 1 receptor and MR to treat hypertension and progression of heart and kidney failure.
Expansion of the classical concept to the new paradigm is characterized by several additional features that subtend aldosterone's role in promoting target organ damage. First in the presence of high-salt (HS) intake, aldosterone produces persistent hypertension with consequent BP-dependent target organ damage. Second, in a permissive milieu with attendant high-sodium intake, even normal concentrations of aldosterone produce BP–independent target organ damage acting through inflammatory and pro-fibrotic pathways.
Metabolic Effects of Aldosterone/MR Activation
Emerging evidence also supports a paradigm shift in our understanding of aldosterone's ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and dysglycemia. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling, which in turn leads to insulin resistance. Indeed, hyperaldosteronism is associated with impaired pancreatic β-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance.
Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the MR. Although we have known that MR blockade attenuates cardiovascular and renal injury, only recently have we learned that MR blockade improves pancreatic insulin release, and insulin-mediated glucose utilization.
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