Angiotensin II Promotes SARS-CoV-2 Infection via Upregulation of ACE2 in Human Bronchial Cells.

Blockers of the renin-angiotensin system (RAS) have been reported to increase the angiotensin converting enzyme (ACE)2, the cellular receptor of SARS-CoV-2, and thus the risk and course of COVID-19. Therefore, we investigated if angiotensin (Ang) II and RAS blockers affected ACE2 expression and SARS-CoV-2 infectivity in human epithelial bronchial Calu-3 cells. By infectivity and spike-mediated cell-cell fusion assays, we showed that Ang II acting on the angiotensin type 1 receptor markedly increased ACE2 at mRNA and protein levels, resulting in enhanced SARS-CoV-2 cell entry. These effects were abolished by irbesartan and not affected by the blockade of ACE-1-mediated Ang II formation with ramipril, and of ACE2- mediated Ang II conversion into Ang 1-7 with MLN-4760. Thus, enhanced Ang II production in patients with an activated RAS might expose to a greater spread of COVID-19 infection in lung cells. The protective action of Angiotensin type 1 receptor antagonists (ARBs) documented in these studies provides a mechanistic explanation for the lack of worse outcomes in high-risk COVID-19 patients on RAS blockers.

Management of hypertensive emergencies: a practical approach.

Background: Acute increases of high blood pressure values, usually described as 'hypertensive crises', 'hypertensive urgencies' or 'hypertensive emergencies', are common causes of patients' presentation to emergency departments. Owing to the lack of ad hoc randomized clinical trials, current recommendations/suggestions for treatment of these patients are not evidenced-based and, therefore, the management of acute increases of blood pressure values represent a clinical challenge. However, an improved understanding of the underlying pathophysiology has changed radically the approach to management of the patients presenting with these conditions in recent years. Accordingly, it has been proposed to abandon the terms 'hypertensive crises' and 'hypertensive urgencies', and restrict the focus to 'hypertensive emergencies'. Aims and Methods: Starting from these premises, we aimed at systematically review all available studies (years 2010-2020) to garner information on the current management of hypertensive emergencies, in order to develop a novel symptoms- and evidence-based streamlined algorithm for the assessment and treatment of these patients.Results and Conclusions: In this educational review we proposed the BARKH-based algorithm for a quick identification of hypertensive emergencies and associated acute organ damage, to allow the patients with hypertensive emergencies to receive immediate treatment in a proper setting.

Arterial Hypertension, Aldosterone, and Atrial Fibrillation.

PURPOSE: Atrial fibrillation is the most common sustained arrhythmia, with a prevalence of 1-2% in the general population and over 15% in people older than 80 years. Due to aging of the population it imposes an increasing burden on the healthcare system because of the need for life-long pharmacological treatment and the associated increased risk of heart failure and hospitalization. Hence, identification of the factors that predispose to atrial fibrillation it is of utmost relevance. RECENT FINDINGS: Several conditions exist that are characterized by inappropriately high levels of aldosterone, mostly primary aldosteronism and the severe or drug-resistant forms of arterial hypertension. In these forms, aldosterone can cause prominent target organ damage, mostly in the heart, vasculature, and kidney. This review examines the experimental data and clinical evidences that support a link between hyperaldosteronism and atrial fibrillation, and how this knowledge should lead to a change in our management of the hypertensive patients presenting with atrial fibrillation.

The Key Role of Epithelial to Mesenchymal Transition (EMT) in Hypertensive Kidney Disease.

Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the 'classic' view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension.

'Essential' arterial hypertension: time for a paradigm change.

The exclusion of causes of hypertension is not systematically exploited in clinical practice. Therefore, essential hypertension is consistently presented as the most prevalent 'cause'. The paradox of a condition with unknown causes being described as a common cause of hypertension translates into a diagnosis of essential hypertension in most patients, which precludes the detection of a curable cause of hypertension. The aim of this review is to investigate how the notion of essential hypertension has developed and whether scientific evidence still support the notion of its high prevalence by examining the most recent studies. These studies provided solid scientific evidence that, when systematically sought for, secondary hypertension is quite common and that secondary hypertension is highly prevalent. The increased awareness should lead to a systematic search for, with the goal of curing or achieving a better control of high blood pressure, and ultimately improving patients' quality of life.

Challenges in the evaluation of endothelial cell dysfunction: a statement from the European Society of Hypertension Working Group on Endothelin and Endothelial Factors.

Endothelial cell function is mediated by different mechanisms in different vascular beds. Moreover, in humans, endothelial cell dysfunction triggers and accelerates the progression of cardiovascular and chronic kidney diseases. Progression of such diseases can be in part mitigated by the control of cardiovascular risk factors and drugs targeting different systems, including endothelin receptor antagonists (ERAs), renin-angiotensin aldosterone antagonists and agents affecting glucose metabolism, all of which were shown to improve endothelial cell function. In recent years, the microRNAs, which are endogenous regulators of gene expression, have been identified as transmitters of information from endothelial cells to vascular smooth muscle cells, suggesting that they can entail tools to assess the endothelial cell dysfunction in arterial hypertension and target for pharmacologic intervention. This article critically reviews current challenges and limitations of available techniques for the invasive and noninvasive assessment of endothelial cell function, and also discusses therapeutic aspects as well as directions for future research in the areas of endothelial cell biology and pathophysiology in humans.

Modern Management of Hypertensive Emergencies.

Acute increases of blood pressure values are common causes of patients' presentation to emergency departments, and their management represents a clinical challenge. They are usually described as 'hypertensive crises', 'hypertensive urgencies', terms that should be abandoned because they are misleading and inappropriate according to a recent task force of the European Society of Cardiology, which recommended to focus only on 'hypertensive emergencies'. The latter can be esasily identified by using the Brain, Arteries, Retina, Kidney, and/or Heart (BARKH) strategy as herein described. Although current guidelines recommendations/suggestions for treatment of these patients are not evidence-based, owing to the lack of randomized clinical trials, improved understanding of the underlying pathophysiology has changed the approach to management of the patients presenting with hypertensive emergencies in recent years. Starting from these premises and a systematic review of the available studies graded by their quality, using the AHA class of recommendation/level of evidence grading, whenever possible, we herein present a novel a streamlined symptoms- and evidence-based algorithm for the assessment and management of patients with hypertensive emergencies.

Drug-resistant hypertension in primary aldosteronism patients undergoing adrenal vein sampling: the AVIS-2-RH study.

AIMS: We aimed at determining the rate of drug-resistant arterial hypertension in patients with an unambiguous diagnosis of primary aldosteronism (PA). Moreover, we sought for investigating the diagnostic performance of adrenal vein sampling (AVS), and the effect of adrenalectomy on blood pressure (BP) and prior treatment resistance in PA patients subtyped by AVS in major referral centres. METHODS AND RESULTS: The Adrenal Vein Sampling International Study-2 (AVIS-2) was a multicentre international study that recruited consecutive PA patients submitted to AVS, according to current guidelines, during 15 years. The patients were over 18 years old with arterial hypertension and had an unambiguous diagnosis of PA. The rate of resistant hypertension was assessed at baseline and after adrenalectomy using the American Heart Association (AHA) 2018 definition. Information on presence or absence of resistant hypertension was available in 89% of the 1625 enrolled PA patients. Based on the AHA 2018 criteria, resistant hypertension was found in 20% of patients, of which about two-thirds (14%) were men and one-third (6%) women (χ2 = 17.1, P < 1*10-4) with a higher rate of RH in men than in women (23% vs. 15% P < 1*10-4). Of the 292 patients with resistant hypertension, 98 (34%) underwent unilateral AVS-guided adrenalectomy, which resolved BP resistance to antihypertensive treatment in all. CONCLUSIONS: (i) Resistant hypertension is a common presentation in patients seeking surgical cure of PA; (ii) AVS is key for the optimal management of patients with PA due to resistant hypertension; and (iii) AVS-guided adrenalectomy allowed resolution of treatment-resistant hypertension.

Disease monitoring of Primary Aldosteronism.

Primary aldosteronism (PA) is a highly prevalent cause of arterial hypertension featuring excess cardiovascular events. A timely diagnosis and treatment of PA cures hyperaldosteronism and can provide resolution or improvement of arterial hypertension, even when the latter is resistant to drug treatment. Accordingly, strategies to screen early and widely the hypertensive patients for PA by means of simplified diagnostic algorithms are justified. Such strategies are particularly beneficial in subgroups of hypertensive patients, who are at the highest cardiovascular risk. Broadening of screening strategies means facing with an increased number of patients where monitoring the disease becomes necessary. Hence, after identification of the surgically and non surgically curable cases of PA and implementation of targeted treatment physicians are faced with the challenges of follow-up, which are scantly discussed in the literature. Hence, the purpose of this paper is to provide some recommendations on how to optimize the monitoring of patients in whom the PA subtype has been diagnosed and treatment, either with unilateral laparoscopic adrenalectomy or medically, has been instituted.

ROCK (RhoA/Rho Kinase) in Cardiovascular-Renal Pathophysiology: A Review of New Advancements.

Rho-associated, coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase and found to belong to the AGC family of serine/threonine kinases. They were shown to be downstream effectors of RhoA and RhoC activation. They signal via phosphorylation of proteins such as MYPT-1, thereby regulating many key cellular functions including proliferation, motility and viability and the RhoA/ROCK signaling has been shown to be deeply involved in arterial hypertension, cardiovascular-renal remodeling, hypertensive nephropathy and posttransplant hypertension. Given the deep involvement of ROCK in cardiovascular-renal pathophysiology and the interaction of ROCK signaling with other signaling pathways, the reports of trials on the clinical beneficial effects of ROCK's pharmacologic targeting are growing. In this current review, we provide a brief survey of the current understanding of ROCK-signaling pathways, also integrating with the more novel data that overall support a relevant role of ROCK for the cardiovascular-renal physiology and pathophysiology.

High Blood Pressure Is Associated with Tubulointerstitial Damage along with Glomerular Damage in Glomerulonephritis. A large Cohort Study.

The key role of arterial hypertension in chonic kidney disease (CKD) progression is widely recognized, but its contribution to tubulointerstitial damage (TID) in glomerulonephritis (GN) remains uncertain. Hence, the objective of this study is to clarify whether TID is associated with glomerular damage, and whether the damage at the tubulointerstitial compartment is more severe in hypertensive patients. The study included retrospectively consecutive patients referred to the Nephrology Unit with diagnoses of primary glomerulonephritis, lupus nephritis (LN), and nephroangiosclerosis (NAS) at biopsy. At least six glomeruli per biopsy were analysed through light and immunofluorescence microscopy. Global glomerulosclerosis (GGS%), TID, and arteriolar hyalinosis (AH) were used as markers of CKD severity. Of the 448 patients of the cohort, 403 received a diagnosis of GN, with the remaining being diagnosed with NAS. Hypertension was found in 52% of the overall patients, with no significant differences among those with GN, and reaching 88.9% prevalence rate in NAS. The hypertensive patients with GN had more marked damage in glomerular and tubular compartments than normotensives independently of the amount of proteinuria. Moreover, hypertension and GGS% were found to be strongly associated with TID in GN. In GN patients, not only the severity of glomerular damage but also the extent of TID was associated with high blood pressure.

Atrial fibrillation as presenting sign of primary aldosteronism: results of the Prospective Appraisal on the Prevalence of Primary Aldosteronism in Hypertensive (PAPPHY) Study.

BACKGROUND: Despite hyperaldosteronism being suggested as predisposing to arrhythmias, the relationship between atrial fibrillation and primary aldosteronism remains uncertain. Therefore, we tested the hypothesis that atrial fibrillation is a presentation of primary aldosteronism in hypertensive patients with unexplained atrial fibrillation. DESIGN AND METHODS: The Prospective Appraisal on the Prevalence of Primary Aldosteronism in Hypertensive (PAPPHY) Study recruited consecutive patients with atrial fibrillation and an unambiguous diagnosis of arterial hypertension at three referral centers for hypertension. RESULTS: In a cohort entailing 411 atrial fibrillation patients, we identified 18% (age 61 ±â€Š11 years; 32% women), who showed no known cause of the arrhythmia. A thorough diagnostic work-up allowed us to identify primary aldosteronism in 73 of these patients, i.e. 42% [95% confidence interval (CI) 31.8-53.9]. Subtyping of primary aldosteronism demonstrated that surgically curable forms of primary aldosteronism accounted for 48% of the cases (95% CI 31.9-65.2). The high prevalence of primary aldosteronism was confirmed at sensitivity analyses. CONCLUSION: These results provided compelling evidence that primary aldosteronism is highly prevalent in hypertensive patients with unexplained atrial fibrillation. Accordingly, they suggest that patients with no identifiable cause of the arrhythmia should be screened for primary aldosteronism to identify those who can be cured or markedly improved with target treatment. CLINICAL TRIAL REGISTRATION: :: https://clinicaltrials.gov, Identifier: NCT01267747.

Role of estrogen receptors in modulating aldosterone biosynthesis and blood pressure.

Blood pressure is lower in premenopausal women than in age-matched men; after menopause blood pressure values and the prevalence of hypertension show opposite trends indicating that estrogens contribute to maintaining normal blood pressure values in women. In experimental studies menopause increases aldosterone levels, an effect alleviated by estrogen treatment. We have recently discovered a role of estrogen receptors (ER) in controlling aldosterone biosynthesis in the human adrenocortical zona glomerulosa, which expresses both the classical ERα and ß receptors and G protein-coupled estrogen receptor (GPER). We have also identified that GPER mediates an aldosterone-induced aldosterone response. We found that 17 ß-estradiol exerts a dual effect: it blunts aldosterone production via ERß, but displays a potent aldosterone secretagogue effect via GPER activation after ERß blockade. Thus, in premenopausal women high estrogen levels might tonically blunt aldosterone synthesis via ERß, thereby maintaining normal blood pressure; after menopause loss of this estrogen-mediated inhibition can contribute to increasing blood pressure via GPER-mediated aldosterone release. The additional findings that GPER mediates an aldosterone-induced stimulation of aldosterone biosynthesis and that GPER predominates in aldosterone-producing adenomas strongly involves this receptor in the pathophysiology of primary aldosteronism. Our purpose here was to provide an update on estrogen receptor function in the normal adrenal cortex and its relevance for the sex differences in blood pressure in light of the newly discovered role of GPER in regulating aldosterone synthesis. The implications of the novel knowledge for the treatment of estrogen-dependent malignancies with ER modulators are also discussed.

Adrenal Venous Sampling: Where Do We Stand?

Adrenal venous sampling is the gold standard test to identify surgically curable primary aldosteronism, but it is markedly underused in clinical practice being perceived as a technically challenging and invasive procedure and, moreover, as difficult to interpret. This review provides updated information on current indications to adrenal venous sampling and how to perform and interpret adrenal venous sampling.

Role of angiotensin II, endothelin-1 and L-type calcium channel in the development of glomerular, tubulointerstitial and perivascular fibrosis.

OBJECTIVE: Fibrosis is a hallmark of renal damage in several diseases, including arterial hypertension. We, therefore, investigated the role of angiotensin II, endothelin-1 and of L-type calcium channels in the development of the glomerular, vascular, and tubulointerstitial fibrosis in a model of severe angiotensin II-dependent hypertension. METHODS: Five-week-old Ren-2 transgenic rats (TGRen2) received for 4 weeks a placebo, bosentan (100 mg/kg body weight), irbesartan (50 mg/kg body weight), the ETA-selective endothelin receptor antagonist BMS-182874 (BMS; 52 mg/kg body weight), the combination of irbesartan (50 mg/kg body weight) plus BMS (52 mg/kg body weight), and nifedipine (30 mg/kg body weight). RESULTS: Glomerular volume, tubulointerstitial fibrosis, glomerular, and perivascular fibrosis were accurately quantified by histomorphometry in four-to-six sections per kidney. Glomerular fibrosis was lowered by BMS (P < 0.001), whereas tubulointerstitial fibrosis was blunted by bosentan (P < 0.001) and irbesartan (P < 0.005). Perivascular fibrosis was reduced by nifedipine and BMS. As only irbesartan and irbesartan plus BMS decreased blood pressure (P < 0.001 vs. placebo), these effects on fibrosis were independent of blood pressure. CONCLUSION: Angiotensin II and L-type calcium channels modulate fibrosis selectively in the tubulointerstitial and in the perivascular compartments, respectively. The prevention of fibrosis with ET-1 receptor antagonism in all three compartments supports a major role of ET-1 in the development of renal fibrosis.

The subtyping of primary aldosteronism by adrenal vein sampling: sequential blood sampling causes factitious lateralization.

BACKGROUND: The pulsatile secretion of adrenocortical hormones and a stress reaction occurring when starting adrenal vein sampling (AVS) can affect the selectivity and also the assessment of lateralization when sequential blood sampling is used. We therefore tested the hypothesis that a simulated sequential blood sampling could decrease the diagnostic accuracy of lateralization index for identification of aldosterone-producing adenoma (APA), as compared with bilaterally simultaneous AVS. METHODS AND RESULTS: In 138 consecutive patients who underwent subtyping of primary aldosteronism, we compared the results obtained simultaneously bilaterally when starting AVS (t-15) and 15 min after (t0), with those gained with a simulated sequential right-to-left AVS technique (R ⇒ L) created by combining hormonal values obtained at t-15 and at t0. The concordance between simultaneously obtained values at t-15 and t0, and between simultaneously obtained values and values gained with a sequential R ⇒ L technique, was also assessed. We found a marked interindividual variability of lateralization index values in the patients with bilaterally selective AVS at both time point. However, overall the lateralization index simultaneously determined at t0 provided a more accurate identification of APA than the simulated sequential lateralization indexR ⇒ L (P = 0.001). Moreover, regardless of which side was sampled first, the sequential AVS technique induced a sequence-dependent overestimation of lateralization index. While in APA patients the concordance between simultaneous AVS at t0 and t-15 and between simultaneous t0 and sequential technique was moderate-to-good (K = 0.55 and 0.66, respectively), in non-APA patients, it was poor (K = 0.12 and 0.13, respectively). CONCLUSION: Sequential AVS generates factitious between-sides gradients, which lower its diagnostic accuracy, likely because of the stress reaction arising upon starting AVS.

The Biology of Normal Zona Glomerulosa and Aldosterone-Producing Adenoma: Pathological Implications.

The identification of several germline and somatic ion channel mutations in aldosterone-producing adenomas (APAs) and detection of cell clusters that can be responsible for excess aldosterone production, as well as the isolation of autoantibodies activating the angiotensin II type 1 receptor, have rapidly advanced the understanding of the biology of primary aldosteronism (PA), particularly that of APA. Hence, the main purpose of this review is to discuss how discoveries of the last decade could affect histopathology analysis and clinical practice. The structural remodeling through development and aging of the human adrenal cortex, particularly of the zona glomerulosa, and the complex regulation of aldosterone, with emphasis on the concepts of zonation and channelopathies, will be addressed. Finally, the diagnostic workup for PA and its subtyping to optimize treatment are reviewed.

Endothelial factors in the pathogenesis and treatment of chronic kidney disease Part I: General mechanisms: a joint consensus statement from the European Society of Hypertension Working Group on Endothelin and Endothelial Factors and The Japanese Society of Hypertension.

: Kidney damage is a common consequence of arterial hypertension, but is also a cause of atherogenesis. Dysfunction and/or harm of the endothelium in glomeruli and tubular interstitium damage the function of these structures and translates into dynamic changes of filtration fraction, with progressive reduction in glomerular filtration rate, expansion of extracellular fluid volume, abnormal ion balance, and hypoxia, ultimately leading to chronic kidney disease. Considering the key role played by endothelial dysfunction in chronic kidney disease, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension have critically reviewed available knowledge on the mechanisms underlying endothelial cell injury. This resulted into two articles: in the first, we herein examine the mechanisms by which endothelial factors induce vascular remodeling and the role of different players, including endothelin-1, the renin-angiotensin-aldosterone system and their interactions, and of oxidative stress; in the second, we discuss the role of endothelial dysfunction in the major disease conditions that affect the kidney.