Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure

Abstract

Abstract-Chronic kidney disease has a tremendously increasing prevalence and requires novel therapeutic approaches.Mineralocorticoid receptor (MR) antagonists have proven highly beneficial in the therapy of cardiac disease. The cellular and molecular events leading to cardiac inflammation and remodeling are proposed to be similar to those mediating renal injury. Thus, this study was designed to evaluate and directly compare the effect of MR deletion in endothelial cells on cardiac and renal injury in a model of deoxycorticosterone acetate-induced hypertension. Endothelial MR deletion ameliorated deoxycorticosterone acetate/salt-induced cardiac remodeling. This was associated with a reduced expression of the vascular cell adhesion molecule Vcam1 in MR-deficient cardiac endothelial cells. Ambulatory blood pressure telemetry revealed that the protective effect of MR deletion was independent from blood pressure. Similar to the heart, deoxycorticosterone acetate/salt-induced severe renal injury, including inflammation, fibrosis, glomerular injury, and proteinuria. However, no differences in renal injury were observed between genotypes. In conclusion, MR deletion from endothelial cells ameliorated deoxycorticosterone acetate/salt-induced cardiac inflammation and remodeling independently from alterations in blood pressure but it did not affect renal injury. These findings suggest that the anti-inflammatory mechanism mediating organ protection after endothelial cell MR deletion is specific for the heart versus the kidney.

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…63 Endothelial MR is essential in the development of not only endothelial dysfunction and hypertension but in mediating hypertensive cardiac injury and dysfunction. 64,65 These phenomena suggest that MR blockade may provide a key strategy to delay and prevent features of cardiovascular aging. Even low, subpressor doses of the MR antagonist, spironolactone prevented aortic and femoral artery stiffening in female mice fed a high-fat/high-sugar western diet, 66 which is particularly important taking into account that vascular stiffening is the main feature of vascular aging.…”

Vascular Mineralocorticoid Receptors

“…Accordingly, EC-MRKO prevented adverse cardiac remodeling in response to mineralocorticoid/salt-induced hypertension in mice. 26,27 This was associated with a downregulation of intercellular cell adhesion molecule or vascular cell adhesion molecule in MR-deficient endothelial cells and less macrophage infiltration of the heart. 26,27 EC-MRKO 4 or treatment with spironolactone 34 protected from high-fat diet-induced macrophage accumulation, oxidative stress, cardiac fibrosis, and diastolic dysfunction.…”

“…24 In contrast, MR deletion from endothelial cells (EC-MRKO) did not alter blood pressure at baseline or in response to mineralocorticoid, mineralocorticoid/salt, or angiotensin II stimulation. 25,26 Vascular relaxation at baseline or after aldosterone treatment was unaltered in mesenteric arteries from MR-deficient mice 25,27 but improved in coronary 25 or aortic 6,27 sections. Obesity and enhanced leptin signaling increased plasma aldosterone levels by 2-to 3-fold in mice.…”

Mineralocorticoid Receptor Signaling as a Therapeutic Target for Renal and Cardiac Fibrosis

“…Studies have shown that deficiency of endothelial MR has no effect on renal injury induced by DOC acetate/salt (Lother et al, 2016) and deficiency of podocyte MR has no effect on the development of anti-glomerular basement membrane (anti-GBM) glomerulonephritis (Huang et al, 2014). In contrast, deficiency of MR in smooth muscle cells has recently been shown to limit ischemia-reperfusion injury in the kidney through effects on Rac1-mediated MR signaling (Barrera-Chimal et al, 2017).…”