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      Pathophysiological mechanisms of mineralocorticoid receptor-dependent cardiovascular and chronic kidney disease

      Hypertension Research

      Springer Nature

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          Abstract

          Accumulating evidence has indicated the potential contributions of aldosterone and mineralocorticoid receptor (MR) to the pathophysiology of cardiovascular disease (CVD) and chronic kidney disease (CKD). Patients with primary aldosteronism have a higher risk of CVD and CKD than those with essential hypertension. MR is strongly expressed in endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts, macrophages, glomerular mesangial cells, podocytes, and proximal tubular cells. In these cardiovascular and renal cells, aldosterone-induced cell injury is prevented by MR blockade. Interestingly, MR antagonists elicit beneficial effects on CVD and CKD in subjects with low or normal plasma aldosterone levels. Recent studies have shown that during development of CVD and CKD, cardiovascular and renal MR is activated by glucocorticoid and ligand-independent mechanisms, such as Rac1 signaling pathways. These data indicate that inappropriate activation of local MR contributes to cardiovascular and renal tissue injury through aldosterone-dependent and -independent mechanisms. In this review, recent findings on the specific role of cardiovascular and renal MR in the pathogenesis of CVD and CKD are summarized.

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          Most cited references 74

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          Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial.

          Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events.
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            Nifedipine controlled-release 40 mg b.i.d. in Japanese patients with essential hypertension who responded insufficiently to nifedipine controlled-release 40 mg q.d.: a phase III, randomized, double-blind and parallel-group study

            This phase III, multicenter, randomized, double-blind, parallel-group study compared the efficacy and safety of nifedipine controlled-release (CR) 40 mg twice daily (b.i.d.) and once daily (q.d.) in 325 Japanese patients with essential hypertension uncontrolled with nifedipine CR 40 mg q.d. (ClinicalTrials.gov record: NCT01287260). The primary endpoint was the change from baseline in trough seated diastolic blood pressure (DBP) after 8 weeks. Nifedipine CR 40 mg b.i.d. showed significantly greater reductions in trough seated DBP (-7.7±0.6 mm Hg vs. -3.6±0.6 mm Hg) and trough seated systolic blood pressure (BP) (-11.1±0.9 mm Hg vs. -3.7±0.9 mm Hg) after 8 weeks of treatment compared with nifedipine CR 40 mg q.d. (both P<0.0001). At week 8, BP target achievement and responder rates were higher with nifedipine CR 40 mg b.i.d. (21.5% and 42.4% vs. 10.3% and 19.5%, respectively). Adverse events considered related to the study drug were reported in 9.0 and 9.7% of patients receiving nifedipine CR 40 mg b.i.d. and q.d., respectively. The frequency of drug-related adverse events commonly reported with nifedipine CR (headache, hot flush, palpitations, peripheral edema, hypotension, dizziness, tachycardia) was low and the results were similar between the treatment groups. In conclusion, a higher dose of nifedipine CR was associated with greater efficacy and a safety profile similar to that of the currently approved dose (40 mg q.d.) in Japanese patients with essential hypertension, and it may offer a valuable treatment choice for patients who do not achieve target BP levels with standard treatment.
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              Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice.

              Inappropriate excess of the steroid hormone aldosterone, which is a mineralocorticoid receptor (MR) agonist, is associated with increased inflammation and risk of cardiovascular disease. MR antagonists are cardioprotective and antiinflammatory in vivo, and evidence suggests that they mediate these effects in part by aldosterone-independent mechanisms. Here we have shown that MR on myeloid cells is necessary for efficient classical macrophage activation by proinflammatory cytokines. Macrophages from mice lacking MR in myeloid cells (referred to herein as MyMRKO mice) exhibited a transcription profile of alternative activation. In vitro, MR deficiency synergized with inducers of alternatively activated macrophages (for example, IL-4 and agonists of PPARgamma and the glucocorticoid receptor) to enhance alternative activation. In vivo, MR deficiency in macrophages mimicked the effects of MR antagonists and protected against cardiac hypertrophy, fibrosis, and vascular damage caused by L-NAME/Ang II. Increased blood pressure and heart rates and decreased circadian variation were observed during treatment of MyMRKO mice with L-NAME/Ang II. We conclude that myeloid MR is an important control point in macrophage polarization and that the function of MR on myeloid cells likely represents a conserved ancestral MR function that is integrated in a transcriptional network with PPARgamma and glucocorticoid receptor. Furthermore, myeloid MR is critical for blood pressure control and for hypertrophic and fibrotic responses in the mouse heart and aorta.
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                Author and article information

                Journal
                Hypertension Research
                Hypertens Res
                Springer Nature
                0916-9636
                1348-4214
                December 6 2018
                Article
                10.1038/s41440-018-0158-6
                30523293
                © 2018

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