Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility

Abstract

Aldosterone blockade confers substantial cardiovascular and renal protection. The effects of aldosterone on mineralocorticoid receptors (MR) expressed in endothelial cells (EC) within the renal vasculature have not been delineated. We hypothesized that lack of MR in EC may be protective in renal vasculature and examined this by ablating the Nr3c2 gene in endothelial cells (EC-MR) in mice. Blood pressure, heart rate and PAH clearance were measured using indwelling catheters in conscious mice. The role of the MR in EC on contraction and relaxation was investigated in the renal artery and in perfused afferent arterioles. Urinary sodium excretion was determined by use of metabolic cages. EC-MR transgenics had markedly decreased MR expression in isolated aortic endothelial cells as compared to littermates (WT). Blood pressure and effective renal plasma flow at baseline and following AngII infusion was similar between groups. No differences in contraction and relaxation were observed between WT and EC-MR KO in isolated renal arteries during baseline or following 2 or 4 weeks of AngII infusion. The constriction or dilatations of afferent arterioles between genotypes were not different. No changes were found between the groups with respect to urinary excretion of sodium after 4 weeks of AngII infusion, or in urinary albumin excretion and kidney morphology. In conclusion, deletion of the EC-MR does not confer protection towards the development of hypertension, endothelial dysfunction of renal arteries or renal function following prolonged AngII-infusion.

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

“…The experimental protocol was approved by the Danish Animal Experiments Inspectorate under the Danish Ministry of Justice (2015-15-0201-00479) and animal care followed the guidelines of the National Institutes of Health in accordance with ARRIVE guidelines. The experimental procedures have been described previously (Andersen et al, 2011;Hansen et al, 2010;Laursen et al, 2018). Mice were anesthetized (100 mg/kg ketamine, 10 mg/kg xylazine) and chronic indwelling catheters were surgically implanted in the femoral artery for measurements of mean arterial blood pressure (MABP) and heart rate (HR), and into the femoral vein for drug infusions.…”

miR-196b-5p-enriched extracellular vesicles from tubular epithelial cells mediated aldosterone-induced renal fibrosis in mice with diabetes

“…29 Although MR is highly expressed in endothelial cells and tubular epithelial cells in the kidney, knockout of the MR gene in endothelial cells did not ameliorate renal injury in AKI and CKD, suggesting that tubular epithelial cells are important for aldosterone-induced kidney injury. 30 Fibroblasts, the main source of ECM, play central importance in TIF. Emerging data have revealed that renal TIF progression also involves other cell types, such as tubular epithelial cells, and growth factors that mediate the crosstalk between these different cellular compartments.…”

Vascular Mineralocorticoid Receptor: Evolutionary Mediator of Wound Healing Turned Harmful by Our Modern Lifestyle

“…In all cases in which renal function was tested, the influence of vascular MR on vessel function appears to be independent of renal mechanisms as neither SMC nor EC MR deletion affected renal sodium handling or salt sensitivity of blood pressure. 8,[22][23][24] In the absence of vascular injury or cardiovascular risk factors, deletion of MR from SMCs or ECs had minimal effect on vasomotor function. However, vascular MR contributes to increased vasomotor tone under conditions of vascular stress.…”

“…28,30,31 In addition to obesity, hypertension induced by AngII or aldosterone also impairs vasomotor function globally that is ameliorated by EC-MR-KO. 8,24,29 Conversely, overexpression of EC-MR induces hypertension with impaired mesenteric vasodilation and enhanced constriction. 9 Similarly, changes in coronary vasoconstriction induced by hypertension are attenuated by EC-MR-KO.…”

“…MR has been found in all vascular beds and vessel sizes tested including the aorta, carotid, coronary, renal, and mesenteric vessels, consistent with a role in global responses to vascular stress via large conduit arteries and small resistance vessels. 8,9 In addition to aldosterone, the stress hormone cortisol circulates in high abundance and can compete with aldosterone for binding to MR. Cortisol is inactivated by 11-beta hydroxysteroid dehydrogenase-2 (11βHSD2)…”