Abstract
Hypertension and its comorbidities pose a major public health problem associated with disease-associated factors related to a modern lifestyle, such high salt intake or obesity. Accumulating evidence has demonstrated that aldosterone and its receptor, the mineralocorticoid receptor (MR), have crucial roles in the development of salt-sensitive hypertension and coexisting cardiovascular and renal injuries. Accordingly, clinical trials have repetitively shown the promising effects of MR blockers in these diseases. We and other researchers have identified novel mechanisms of MR activation involved in salt-sensitive hypertension and renal injury, including the obesity-derived overproduction of aldosterone and ligand-independent signaling. Moreover, recent advances in the analysis of cell-specific and context-dependent mechanisms of MR activation in various tissues-including a classic target of aldosterone, aldosterone-sensitive distal nephrons-are now providing new insights. In this review, we summarize recent updates to our understanding of aldosterone-MR signaling, focusing on its role in salt-sensitive hypertension and renal injury.
Highlights
Aldosterone, secreted from adrenal glands by stimuli including angiotensin II (AngII) or hyperkalemia, binds to the mineralocorticoid receptor (MR) expressed on epithelial cells in the aldosterone-sensitive distal nephron (ASDN) to regulate sodium and potassium flux.1–3 According to the theory that renal handling of sodium is a key determinant of fluid volume and BP control,4,5 MR signaling in the connecting tubule and collecting duct is essential for the regulation of BP, especially in the development of salt-sensitive hypertension.6 Mutations in aldosterone synthase in the MR or in a major target of MR signaling, the epithelial sodium channel (ENaC), cause genetic disorders with hypertension or hypotension.7 Higher aldosterone levels within the physiologic range were associated with hypertension in a community-based study.8 aldosterone administration in canines shifted the pressure-natriuresis curve, indicating salt-sensitive hypertension.9
According to the theory that renal handling of sodium is a key determinant of fluid volume and BP control,4,5 mineralocorticoid receptor (MR) signaling in the connecting tubule and collecting duct is essential for the regulation of BP, especially in the development of salt-sensitive hypertension
In contrast to obese SHR rats, despite adequately suppressed plasma aldosterone, Dahl saltsensitive (Dahl-S) rats, a classic model of salt-sensitive hypertension, develop hypertension and proteinuric renal injury after salt loading, along with increased MR signaling in kidneys that www.jasn.org REVIEW
Summary
Aldosterone, secreted from adrenal glands by stimuli including angiotensin II (AngII) or hyperkalemia, binds to the mineralocorticoid receptor (MR) expressed on epithelial cells in the aldosterone-sensitive distal nephron (ASDN) to regulate sodium and potassium flux.1–3 According to the theory that renal handling of sodium is a key determinant of fluid volume and BP control,4,5 MR signaling in the connecting tubule and collecting duct is essential for the regulation of BP, especially in the development of salt-sensitive hypertension.6 Mutations in aldosterone synthase in the MR or in a major target of MR signaling, the epithelial sodium channel (ENaC), cause genetic disorders with hypertension or hypotension.7 Higher aldosterone levels within the physiologic range were associated with hypertension in a community-based study.8 aldosterone administration in canines shifted the pressure-natriuresis curve, indicating salt-sensitive hypertension.9.
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