Mineralocorticoid Receptor-Associated Hypertension and Its Organ Damage: Clinical Relevance for Resistant Hypertension

Abstract

The role of aldosterone in the pathogenesis of hypertension and cardiovascular diseases has been clearly shown in congestive heart failure and endocrine hypertension due to primary aldosteronism. In resistant hypertension, defined as a failure of concomitant use of three or more different classes of antihypertensive agents to control blood pressure (BP), add-on therapy with mineralocorticoid receptor (MR) antagonists is frequently effective, which we designate as "MR-associated hypertension". The MR-associated hypertension is classified into two subtypes, that with elevated plasma aldosterone levels and that with normal plasma aldosterone levels. The former subtype includes primary aldosteronism (PA), aldosterone-associated hypertension which exhibited elevated aldosterone-to-renin ratio and plasma aldosterone levels, but no PA, aldosterone breakthrough phenomenon elicited when angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) is continued to be given, and obstructive sleep apnea. In contrast, the latter subtype includes obesity, diabetes mellitus, chronic kidney disease (CKD), and polycystic ovary syndrome (PCOS). The pathogenesis of MR-associated hypertension with normal plasma aldosterone levels is considered to be mediated by MR activation by pathways other than high aldosterone levels, such as increased MR levels, increased MR sensitivity, and MR overstimulation by other factors such as Rac1. For resistant hypertension with high plasma aldosterone levels, MR antagonist should be given as a first-line therapy, whereas for resistant hypertension with normal aldosterone levels, ARB or ACE-I should be given as a first-line therapy and MR antagonist would be given as an add-on agent.

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

“…Multiple factors regulate sodium balance; in this study, we focused on mineralocorticoid receptor (MR). In recent studies, we identified novel coregulators of MR3, 4 and proposed a new pathological condition associated with aberrant MR activation, designated MR‐associated hypertension 5…”

Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease

“…1 They can also suppress kidney damage in animal models of GN and diabetic nephropathy without affecting BP. [2][3][4][5][6] In addition, MR antagonists provide added protection against proteinuria and loss of renal function when used with standard antihypertensive therapies in patients with diabetic and nondiabetic CKD.…”

Apparent Treatment-Resistant Hypertension and Chronic Kidney Disease: Another Cardiovascular-Renal Syndrome?

“…21,22 The widespread locations of the MR are thought to explain the pleiotropic effects of aldosterone, including salt reabsorption, cardiac fibrosis, and vascular hypertrophy and inflammation resulting in reduced NO availability. Vascular inflammation leads to vascular fibrosis, whereas NO reduction leads to endothelial dysfunction and vasoconstriction.…”

“…In the setting of CKD, the small GTPase protein Rac-1 also increases MR activation, causing hypertension. 22 Thus, MR-mediated hypertension is possible even in patients with normal aldosterone concentrations. Indeed, among 1688 nonhypertensive patients in the Framingham Heart Study, baseline plasma aldosterone levels predicted progression to hypertension, even among patients with normal aldosterone concentrations at baseline.…”