Adipocytes, aldosterone and obesity-related hypertension

Understanding the mechanisms linking obesity with hypertension is important in the current obesity epidemic as it may improve therapeutic interventions. Plasma aldosterone levels are positively correlated with body mass index and weight loss in obese patients is reported to be accompanied by decreased aldosterone levels. This suggests a relationship between adipose tissue and the production/secretion of aldosterone. Aldosterone is synthesized principally by the adrenal glands, but its production may be regulated by many factors, including factors secreted by adipocytes. In addition, studies have reported local synthesis of aldosterone in extra-adrenal tissues, including adipose tissue. Experimental studies have highlighted a role for adipocyte-secreted aldosterone in the pathogenesis of obesity-related cardiovascular complications via the mineralocorticoid receptor. This review focuses on how aldosterone secretion may be influenced by adipose tissue and the importance of these mechanisms in the context of obesity-related hypertension

Brown adipose tissue regulates small artery function through NADPH oxidase 4-derived hydrogen peroxide and redox-sensitive protein kinase G-1α

Objective—Biomedical interest in brown adipose tissue (BAT) has increased since the discovery of functionally active BAT in adult humans. Although white adipose tissue (WAT) influences vascular function, vascular effects of BAT are elusive. Thus, we investigated the regulatory role and putative vasoprotective effects of BAT, focusing on hydrogen peroxide, nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4), and redox-sensitive signaling. Approach and Results—Vascular reactivity was assessed in wild-type and Nox4-knockout mice (Nox4−/−) by wire myography in the absence and presence of perivascular adipose tissue of different phenotypes from various adipose depots: (1) mixed WAT/BAT (inguinal adipose tissue) and (2) WAT (epididymal visceral fat) and BAT (intrascapular fat). In wild-type mice, epididymal visceral fat and perivascular adipose tissue increased EC50 to noradrenaline without affecting maximum contraction. BAT increased EC50 and significantly decreased maximum contraction, which were prevented by a hydrogen peroxide scavenger (polyethylene glycated catalase) and a specific cyclic GMP–dependent protein kinase G type-1α inhibitor (DT-3), but not by inhibition of endothelial nitric oxide synthase or guanylate cyclase. BAT induced dimerization of cyclic GMP–dependent protein kinase G type-1α and reduced phosphorylation of myosin light chain phosphatase subunit 1 and myosin light chain 20. BAT from Nox4-knockout mice displayed reduced hydrogen peroxide levels and no anticontractile effects. Perivascular adipose tissue from β3 agonist–treated mice displayed browned perivascular adipose tissue and an increased anticontractile effect. Conclusions—We identify a novel vasoprotective action of BAT through an anticontractile effect that is mechanistically different to WAT. Specifically, BAT, via Nox4-derived hydrogen peroxide, induces cyclic GMP–dependent protein kinase G type-1α activation, resulting in reduced vascular contractility. BAT may constitute an interesting therapeutic target to restore vascular function and prevent vascular complications in cardiovascular diseases

Determinants of renal oxygen metabolism during low Na+ diet : effect of angiotensin II AT1 and aldosterone receptor blockade

Reducing Na(+)intake reduces the partial pressure of oxygen in the renal cortex and activates the renin-angiotensin-aldosterone system. In the absence of high blood pressure, these consequences of dietary Na(+)reduction may be detrimental for the kidney. In a normotensive animal experimental model, reducing Na(+)intake for 2 weeks increased renal oxygen consumption, which was normalized by mineralocorticoid receptor blockade. Furthermore, blockade of the angiotensin II AT(1)receptor restored cortical partial pressure of oxygen by improving oxygen delivery. This shows that increased activity of the renin-angiotensin-aldosterone system contributes to increased oxygen metabolism in the kidney after 2 weeks of a low Na(+)diet. The results provide insights into dietary Na(+)restriction in the absence of high blood pressure, and its consequences for the kidney. Reduced Na(+)intake reduces thePO2(partial pressure of oxygen) in the renal cortex. Upon reduced Na(+)intake, reabsorption along the nephron is adjusted with activation of the renin-angiotensin-aldosterone system (RAAS). Thus, we studied the effect of reduced Na(+)intake on renal oxygen homeostasis and function in rats, and the impact of intrarenal angiotensin II AT(1)receptor blockade using candesartan and mineralocorticoid receptor blockade using canrenoic acid potassium salt (CAP). Male Sprague-Dawley rats were fed standard rat chow containing normal (0.25%) and low (0.025%) Na(+)for 2 weeks. The animals were anaesthetized (thiobutabarbital 120 mg kg(-1)) and surgically prepared for kidney oxygen metabolism and function studies before and after acute intrarenal arterial infusion of candesartan (4.2 mu g kg(-1)) or intravenous infusion of CAP (20 mg kg(-1)). Baseline mean arterial pressure and renal blood flow were similar in both dietary groups. Fractional Na(+)excretion and cortical oxygen tension were lower and renal oxygen consumption was higher in low Na(+)groups. Neither candesartan nor CAP affected arterial pressure. Renal blood flow and cortical oxygen tension increased in both groups after candesartan in the low Na(+)group. Fractional Na(+)excretion was increased and oxygen consumption reduced in the low Na(+)group after CAP. These results suggest that blockade of angiotensin II AT(1)receptors has a major impact upon oxygen delivery during normal and low Na(+)conditions, while aldosterone receptors mainly affect oxygen metabolism following 2 weeks of a low Na(+)diet.List of authors in thesis manuscript: Daniela Patinha, Carla Carvalho, Patrick Persson, Liselotte Pihl, Julie O'Niell, Fredrik Palm</p