| | |  | | NEWSLETTER ::: NO. 16 ::: JUNE 2018 | | FELIX BEUSCHLEIN: IT TAKES TWO TO TANGO | | High blood pressure is very common. It is often triggered by chronic activation of the renin–angiotensin– aldosterone system (RAAS), which plays an important role in the regulation of blood volume and arterial pressure and interlinks the kidneys and the adrenal glands. |  | | Renal experts are currently exploring molecular mechanisms and environmental factors that cause chronic RAAS activation.
Depending on age group, 10 to 40 per cent of the population are affected by high blood pressure (hypertension), which can lead to fatal cardiovascular diseases. One major cause of hypertension is the chronic activation of the renin–angiotensin–aldosterone system (RAAS). This system regulates blood pressure, fluid volume and the vascular response to injury and inflammation. It also interlinks two main organs—the kidneys and the adrenal glands. Chronic RAAS activation leads to persistent hypertension, setting off a cascade of inflammatory, thrombotic and atherogenic effects eventually leading to end-organ damage. Numerous studies have demonstrated that elevated renin and/or aldosterone levels are predictors of adverse outcomes in hypertension, and of heart failure, myocardial infarction and chronic kidney disease, and influence insulin resistance.
Finding the cause
RAAS activation can be induced on several levels: for example, renal artery stenosis results in increased renin secretion, which leads to high aldosterone output from the adrenal zona glomerulosa cells, which are the source of aldosterone secretion. And there are other reasons for a dysregulated RAAS based on adrenal aldosterone, and one is—at least in part—independent of the upstream stimulation of renin and angiotensin. In fact, this condition—known as primary aldosteronism (PA)—is the most common secondary form of hypertension, with an estimated prevalence of between 4 and 12 per cent of hypertensives and 11 to 20 per cent of patients being resistant to combined antihypertensive medication. PA is currently acknowledged to be the most common curable form of hypertension.
The two predominant causes of dysregulated aldosterone secretion are aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia (BAH). Once a patient is diagnosed with PA, it is important to distinguish between the surgically correctable forms (APA and unilateral primary adrenal hyperplasia) and forms that should be treated pharmacologically (BAH).
Tracing molecular mechanisms
In the last decade, several mutations in channels, transporters and enzymes (KCNJ5, ATP1A1, ATP2B3, CACNA1H, CACNA1D and CLCN2) have been linked to the development of APA and familial forms of PA. These mutations are thought to trigger inappropriate shifts in intracellular ion content, which ultimately leads to an excess of aldosterone. Yet we still have only limited knowledge of the molecular mechanisms that link abnormal intracellular signaling and increased steroid production, and particularly adrenocortical cell proliferation.
Current hypotheses regarding these molecular mechanisms have been inferred from the physiological action of stimulators of steroidogenesis. Remarkably, the signaling pathways of aldosterone secretagogues include the regulation of the activity of protein kinases, ultimately promoting hormonal output. Aldosterone stimulating factors, such as AngII and K+, depolarise the membrane voltage of zona glomerulosa cells, triggering intracellular Ca2+ signaling that is thought to activate several members of the calmodulin kinase family. Moreover, AngII also promotes the release of Ca2+ from intracellular stores via IP3 and stimulates the protein kinase C and D families via the production of diacylglycerol.
Calcium signaling activates the steroidogenic acute regulatory protein (StAR), which translocates cholesterol from the outer towards the inner mitochondrial membrane and is regarded as one of the rate-limiting steps for adrenocortical steroid production. Members of the calmodulin kinase family that are activated by Ca2+ further regulate several transcription factors, ultimately promoting the expression of CYP11B2 (coding for aldosterone synthase), the terminal enzyme involved in the biosynthesis of aldosterone.
The genetic and molecular contributors of around 50 per cent of all APA cases can currently be delineated. Despite these achievements, there has been only minor progress in translating this knowledge into clinical practice. Moreover, somatic mutations causative of APAs have also been identified in a high proportion of adrenal glands from healthy kidney donors and from autopsy series. Due to the lack of animal models closely resembling the human phenotype, questions such as why some adrenal cells carrying APA-related somatic mutations develop into APAs while others do not, or what are the effects of aldosterone overproduction on the renal and cardiovascular system in this particular context, remain understudied.
Diet influences blood pressure
Various environmental factors including salt intake effect both the kidney and the adrenal gland, which collectively dictate blood pressure control. Another such factor is dietary potassium intake. This effects kidney function directly as well as through modulating adrenal zona glomerulosa cells, which are very sensitive to changes in extracellular potassium concentration. In fact, high dietary potassium intake in wild type mice is associated with robust changes in the transcriptional profile of their adrenal glands. Potassium excretion from the kidney is also further increased through aldosterone, which results in a feedback loop in addition to that of the RAA system.
To improve blood pressure control it is important to further study mechanisms in a suitable experimental setting that takes into account the multiple layers of regulatory networks. It is clear that insights into the physiology and pathophysiology of blood pressure control will remain incomplete if they do not consider environmental factors and molecular mechanisms or if research is restricted to an organ-centric view. After all, it needs at least two—the kidney and the adrenal gland—to tango.
| | | Felix Beuschlein Felix Beuschlein is an endocrinologist and Clinic Director of the Department of Endocrinology, Diabetology and Clinical Nutrition at the University Hospital Zurich. He is currently a member of the Executive Committee of the European Society of Endocrinology. His research focus is the diseases of the adrenals and the pituitary gland. |
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| | | | Kidney - Control of Homeostasis | | is a Swiss research initiative, headquartered at University of Zurich, which brings together leading specialists in experimental and clinical nephrology and physiology from the universities of Bern, Fribourg, Geneva, Lausanne, and Zurich, and corresponding university hospitals. |
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