Renin Release Research Articles

Effects of Renin-Angiotensin-Aldosterone System Inhibition on Left Ventricular Hypertrophy, Diastolic Function, and Functional Status in Patients With Hypertrophic Cardiomyopathy: A Systematic Review.

The renin-angiotensin-aldosterone system (RAAS) plays a vital role in cardiovascular homeostasis by regulating blood pressure, salt, and water balance. The kidneys produce renin which converts angiotensinogen to angiotensin-1 (AT-I) and angiotensin-converting enzyme (ACE) to angiotensin-II (AT-II). AT-II binds to receptors in the adrenal cortex to release aldosterone. AT-II and aldosterone promote water and salt retention, vascular tone, and myocardial contractility. These physiological changes raise blood pressure and circulation. Reduced renal perfusion pressure sensed by baroreceptors and the sympathetic nervous system’s β-adrenergic receptors trigger renin release and RAAS activation. RAAS restores hemodynamic stability in pathological states associated with low perfusion. This adaptive response is important for restoring perfusion and hemodynamic stability, but prolonged RAAS activation has deleterious effects on the cardiovascular system. Long-term mineralocorticoid exposure has been linked to left ventricular hypertrophy (LVH) and remodeling. AT-II activates fibroblasts and cardiac myocytes to promote cardiac remodeling. Blocking RAAS can eliminate the long-term negative effects of RAAS activation. Direct renin inhibitors, ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists are RAAS blockers.RAAS blockade improves mortality and hospitalization in systolic heart failure and acute myocardial infarction. RAAS blockade has not demonstrated the same benefits in other cardiac populations, such as those with preserved ejection fraction. Hypertrophic cardiomyopathy (HCM) causes LVH and asymmetric septal hypertrophy. When the outflow tract gradient exceeds 30 mmHg and is associated with septal hypertrophy, it is known as obstructive HCM. Dyspnea on exertion, syncope, and exertional angina are symptoms of HCM. RAAS activation worsens LVH by increasing blood pressure and by directly affecting cardiac myocytes with AT-II and aldosterone. RAAS blockade reverses myocardial fibrosis and slows HCM progression in animal models. We performed a meta-analysis of randomized clinical trials to further investigate the potential benefit of RAAS blockade in HCM patients. Although our findings included significant results for some of the RAAS blockade agents, these findings were not consistent throughout all the studies. Mavacamten, one of the newest treatments, has shown promising outcomes.

RENIN, ERYTHROPOIETIN AND VITAMIN D RELEASE FROM HUMAN DONOR KIDNEYS DURING NORMOTHERMIC MACHINE PERFUSION: PREDICTORS OF POST-TRANSPLANTATION OUTCOME?

Objective: Normothermic (37C) machine perfusion (NMP) is a potential alternative to currently used hypothermic (4C) machine perfusion (HMP) for donor kidney preservation before transplantation. NMP allows for metabolic activity and for functional assessment of donor kidneys. The kidneys are key producers of hormones and we investigated the release of prorenin/renin, erythropoietin (EPO), and vitamin D by kidneys on machine perfusion. Design and method: Ten donor kidneys were subjected to HMP followed by 2 h of oxygenated NMP before transplantation. NMP perfusate was collected at three time points (0 h, 1 h, 2 h). Ten HMP perfusate samples were collected for the same measurements. Results: Median release rates of prorenin (196 [i.q.r 28–266] ng/hour) and renin (228 [94–302] ng/hour) in the first hour of NMP were 83- and 37-fold higher than that in HMP perfusates respectively (p = 0.0009 and p < 0.0001). Median renin release rate showed a 3.2-fold downregulation during the second hour of NMP compared to the first hour. Median EPO release rate (14 [i.q.r 8–48] mIU/min) during the first hour of NMP was 2.9-fold higher than that in HMP perfusates (p = 0.035), while it remained stable in the second hour of NMP. Active vitamin D was undetectable in HMP perfusate samples, while there was a median vitamin D secretion of 56 (i.q.r 30–83) and 28 (8–50) pmol/hour in the first and second hour of NMP respectively (p = 0.0001 and p = 0.003). We then investigated whether there were correlations between the hormone releasing capacity and donor kidney status. Prorenin release rate in the second hour of NMP was lower as cold ischemia time (CIT) until NMP of donor kidneys increased (r = -0.605; p = 0.049). EPO release showed no correlation with donor age or CIT. Donor age and vitamin D release rate during two hours of NMP are highly correlated (r = 0.652; p = 0.034). Interestingly, donation after brain death (DBD) kidneys significantly released more vitamin D than donation after circulatory death (DCD) kidneys during the first and second hour of NMP (p = 0.024 and p = 0.012). Conclusions: These data shows that NMP increases the hormone release capacity of transplant kidneys. Hormone release may represent a tool to assess kidney function during NMP.

Targeting and Modulation of the Natriuretic Peptide System in Covid-19: A Single or Double-Edged Effect?

Natriuretic peptide system (NPS) is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and natriuretic peptide precursor C (NPC), that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase (NEP), also known as neprilysin. Coronavirus disease 2019 (Covid-19) pandemic may lead to acute lung injury (ALI) and/or respiratory distress syndrome (ARDS). The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs and may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in managing Covid-19.

New Insights into Juxtaglomerular Cells via Single‐Cell RNA‐Sequencing

The regulation of renin release from juxtaglomerular (JG) cells at the systemic or local level has been extensively investigated and well understood. It includes three primary mechanisms: intrarenal baroreceptor, salt feedback via macula densa, and β1‐adrenergic receptor activation. However, further understanding of the control of renin synthesis and secretion in JG cells at the cellular or molecular level is limited. Additionally, JG cells are generally considered to be derived from the smooth muscle (SM) cells in the afferent arterioles via a reversible metaplastic transformation. The number of JG cells could be significantly increased under specific conditions, which is also known as the process of JG cells recruitment. Nevertheless, the similarities and differences at the molecular level between JG cells and SM cells as well as the intracellular mechanisms underlying the JG cells recruitment have not been fully clarified. An emerging technique, the single‐cell RNA sequencing, provides a new tool to precisely investigate the molecular characterization of JG cells. In the present study, we isolated and sequenced a total of 9815 cells from a single‐cell stock derived from the renal cortex of C57BL/6J mice (~20 mg cortical tissue per mouse, n=5). Using stringent quality controls, we further analyzed 7557 cells. Unbiased clustering analysis demonstrated 16 distinct cell clusters in the t‐distributed stochastic neighbor embedding (tSNE) map, and each cell cluster was defined based on the expression level of the representative cell type‐specific marker genes. In particular, a cluster consisting of 284 cells was identified as smooth muscle (SM) cells by the high and distinct expression of both Acta2 (α‐smooth muscle actin) and Tagln (Transgelin). Moreover, on the basis of the expression level of the marker gene Ren1 (Renin), 34 JG cells were further distinguished from this cluster of SM cells. We profiled the whole‐transcriptome of these JG cells and correlated it with the transcriptional level of Ren1. The top 5 genes that were most positively correlated with the Ren1 expression were Nr2f1 (R=0.79), Akr1b7 (R=0.68), Smim15 (R=0.64), Gng11 (R=0.60) and Sdc1 (R=0.59). We also compared the whole‐transcriptome between these JG cells and SM cells. The top 5 genes with the largest difference in the normalized transcript count were Ren1 (+4.28), Akr1b7 (+1.53), Sfrp2 (+1.01), Fam46a (+0.88), and Sdc1 (+0.75). Thus, aldo‐keto reductase 1B7 (Akr1b7) and syndecan‐1 (Sdc1) could be two potential candidates that may participate in the control of renin release from JG cells. However, previous studies using the Akr1b7‐deficient mice have shown that aldo‐keto reductase 1B7 is not of major relevance for the modulation of renin production and secretion. Therefore, we speculate that syndecan‐1 (Sdc1), a transmembrane heparan sulfate proteoglycan, may play a role in the regulation of renin release as well as JG cells recruitment, especially through the mechanism of intrarenal baroreceptor. This hypothesis will be tested with the Sdc1‐deficient mouse model in our future studies.

Piezo2 expression and its alteration by mechanical forces in mouse mesangial cells and renin-producing cells

The kidney plays a central role in body fluid homeostasis. Cells in the glomeruli and juxtaglomerular apparatus sense mechanical forces and modulate glomerular filtration and renin release. However, details of mechanosensory systems in these cells are unclear. Piezo2 is a recently identified mechanically activated ion channel found in various tissues, especially sensory neurons. Herein, we examined Piezo2 expression and regulation in mouse kidneys. RNAscope in situ hybridization revealed that Piezo2 expression was highly localized in mesangial cells and juxtaglomerular renin-producing cells. Immunofluorescence assays detected GFP signals in mesangial cells and juxtaglomerular renin-producing cells of Piezo2GFP reporter mice. Piezo2 transcripts were observed in the Foxd1-positive stromal progenitor cells of the metanephric mesenchyme in the developing mouse kidney, which are precursors of mesangial cells and renin-producing cells. In a mouse model of dehydration, Piezo2 expression was downregulated in mesangial cells and upregulated in juxtaglomerular renin-producing cells, along with the overproduction of renin and enlargement of the area of renin-producing cells. Furthermore, the expression of the renin coding gene Ren1 was reduced by Piezo2 knockdown in cultured juxtaglomerular As4.1 cells under static and stretched conditions. These data suggest pivotal roles for Piezo2 in the regulation of glomerular filtration and body fluid balance.

Thyroid hormone increases oxygen metabolism causing intrarenal tissue hypoxia; a pathway to kidney disease.

The proposed mechanisms for the development of nephropathy are many, complex and often overlapping. Although recent literature strongly supports a role of kidney hypoxia as an independent pathway to nephropathy, the evidence remains inconclusive since the role of hypoxia is difficult to differentiate from confounding factors such as hyperglycemia, hypertension and oxidative stress. By increasing kidney oxygen consumption using triiodothyronine (T3) and, thus, avoiding these confounding factors, the aim of the present study was to investigate renal hypoxia per se as a causal pathway for the development of nephropathy. Healthy Sprague-Dawley rats were treated with T3 (10 μg/kg/day) and the angiotensin II AT1-receptor antagonist candesartan (1 mg/kg in drinking water) to eliminate effects of T3-induced renin release; and compared to a candesartan treated control group. After 7 weeks of treatment in vivo kidney function, oxygen metabolism and mitochondrial function were evaluated. T3 did not affect glomerular filtration rate or renal blood flow, but increased total kidney oxygen consumption resulting in cortical hypoxia. Nephropathy, demonstrated as albuminuria and tubulointerstitial fibrosis, developed in T3-treated animals. Mitochondria uncoupling mediated by uncoupling protein 2 and the adenosine nucleotide transporter was demonstrated as a mechanism causing the increased kidney oxygen consumption. Importantly, blood glucose levels, mean arterial blood pressure and oxidative stress levels were not affected by T3. In conclusion, the present study provides further evidence for increased kidney oxygen consumption causing intrarenal tissue hypoxia, as a causal pathway for development of nephropathy.

Arachidonic Acid as Mechanotransducer of Renin Cell Baroreceptor.

For normal maintenance of blood pressure and blood volume a well-balanced renin-angiotensin-aldosterone system (RAS) is necessary. For this purpose, renin is secreted as the situation demands by the juxtaglomerular cells (also called as granular cells) that are in the walls of the afferent arterioles. Juxtaglomerular cells can sense minute changes in the blood pressure and blood volume and accordingly synthesize, store, and secrete appropriate amounts of renin. Thus, when the blood pressure and blood volume are decreased JGA cells synthesize and secrete higher amounts of renin and when the blood pressure and blood volume is increased the synthesis and secretion of renin is decreased such that homeostasis is restored. To decipher this important function, JGA cells (renin cells) need to sense and transmit the extracellular physical forces to their chromatin to control renin gene expression for appropriate renin synthesis. The changes in perfusion pressure are sensed by Integrin β1 that is transmitted to the renin cell’s nucleus via lamin A/C that produces changes in the architecture of the chromatin. This results in an alteration (either increase or decrease) in renin gene expression. Cell membrane is situated in an unique location since all stimuli need to be transmitted to the cell nucleus and messages from the DNA to the cell external environment can be conveyed only through it. This implies that cell membrane structure and integrity is essential for all cellular functions. Cell membrane is composed to proteins and lipids. The lipid components of the cell membrane regulate its (cell membrane) fluidity and the way the messages are transmitted between the cell and its environment. Of all the lipids present in the membrane, arachidonic acid (AA) forms an important constituent. In response to pressure and other stimuli, cellular and nuclear shape changes occur that render nucleus to act as an elastic mechanotransducer that produces not only changes in cell shape but also in its dynamic behavior. Cell shape changes in response to external pressure(s) result(s) in the activation of cPLA2 (cytosolic phospholipase 2)-AA pathway that stretches to recruit myosin II which produces actin-myosin cytoskeleton contractility. Released AA can undergo peroxidation and peroxidized AA binds to DNA to regulate the expression of several genes. Alterations in the perfusion pressure in the afferent arterioles produces parallel changes in the renin cell membrane leading to changes in renin release. AA and its metabolic products regulate not only the release of renin but also changes in the vanilloid type 1 (TRPV1) expression in renal sensory nerves. Thus, AA and its metabolites function as intermediate/mediator molecules in transducing changes in perfusion and mechanical pressures that involves nuclear mechanotransduction mechanism. This mechanotransducer function of AA has relevance to the synthesis and release of insulin, neurotransmitters, and other soluble mediators release by specialized and non-specialized cells. Thus, AA plays a critical role in diseases such as diabetes mellitus, hypertension, atherosclerosis, coronary heart disease, sepsis, lupus, rheumatoid arthritis, and cancer.

FREQUENCE OF JUXTAGLOMERULAR GRANULATED CELIS IN DEHYDRATED AND SODIUM-LOADED MICE

Fifteen albino mice were subjected to three days dehydration and fifteen albino mice were given 1% NaCl in their drinking water. Control animals were given drinking water 
 All animals were sacrificed and kidneys were fixed in different fixatives and processed for light microscopy 
 Section were stained for juxtaglomerular cells demonstration and the juxtaglomerular index (GI) and percentage of granulated nephron(%GN) were calculated. Kidneys from dehydrated and sodium-loaded animals showed significant decrease in both JGI and % GN and was discussed in relation to renin secretion and release.

Hydrogen Sulfide and the Kidney: Physiological Roles, Contribution to Pathophysiology, and Therapeutic Potential.

Significance: Hydrogen sulfide (H2S), the third member of the gasotransmitter family, has a broad spectrum of biological activities, including antioxidant and cytoprotective actions, as well as vasodilatory, anti-inflammatory and antifibrotic effects. New, significant aspects of H2S biology in the kidney continue to emerge, underscoring the importance of this signaling molecule in kidney homeostasis, function, and disease. Recent Advances: H2S signals via three main mechanisms, by maintaining redox balance through its antioxidant actions, by post-translational modifications of cellular proteins (S-sulfhydration), and by binding to protein metal centers. Important renal functions such as glomerular filtration, renin release, or sodium reabsorption have been shown to be regulated by H2S, using either exogenous donors or by the endogenous-producing systems. Critical Issues: Lower H2S levels are observed in many renal pathologies, including renal ischemia-reperfusion injury and obstructive, diabetic, or hypertensive nephropathy. Unraveling the molecular targets through which H2S exerts its beneficial effects would be of great importance not only for understanding basic renal physiology, but also for identifying new pharmacological interventions for renal disease. Future Directions: Additional studies are needed to better understand the role of H2S in the kidney. Mapping the expression pattern of H2S-producing and -degrading enzymes in renal cells and generation of cell-specific knockout mice based on this information will be invaluable in the effort to unravel additional roles for H2S in kidney (patho)physiology. With this knowledge, novel targeted more effective therapeutic strategies for renal disease can be designed. Antioxid. Redox Signal. 36, 220-243.

Effect of diuretics on plasma aldosterone and potassium in primary hypertension: A systematic review and meta-analysis.

By contrast with drugs inhibiting the renin-angiotensin-aldosterone system (RAAS), diuretics stimulate renin release by the kidneys. Although plasma aldosterone (PA) is thought to be mainly regulated by RAAS activity, serum potassium has been shown to be an important factor in animal models and humans. Here we perform a systematic review and meta-analysis of randomised controlled trials (RCT) in hypertension investigating the effects of diuretic therapy on PA and the correlation of change in PA with that of potassium and blood pressure (BP). Three databases were searched: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Titles were first screened by title and abstract for relevance before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. A total of 1139 articles were retrieved, of which 42 met the prespecified inclusion/exclusion criteria. The average standardised difference in mean PA was similar for all classes of diuretic: thiazide/thiazide-like 0.299 (95% confidence interval [CI] 0.150, 0.447), loop 0.927 (0.37, 1.49), MRA/potassium-sparing 0.265 (0.173, 0.357) and combination 0.466 (0.137, 0.796), Q = 6.33, P = .097. In subjects untreated with another antihypertensive, there was a significant relationship between change in PA and change in systolic BP but no relationship with the change in potassium. In RCTs of diuretic therapy in hypertension, there is an increase in PA with all classes of diuretic and no significant between-class heterogeneity. Change in PA is not related with potassium but correlates with the change in BP in subjects untreated with another antihypertensive medication.

Renal denervation alters ambulatory blood pressure-derived salt sensitivity index in patients with uncontrolled hypertension.

Renal denervation (RDN) has been proven in multiple sham-controlled trials to lower blood pressure (BP) in various forms of hypertension. RDN-mediated interruption of sympathetic signaling through its effects on renal blood flow, salt retention, and renin release are likely contributors to the BP-lowering effects. However, the impact of RDN on salt sensitivity in humans has not yet been explored. We, therefore, investigated the effect of RDN on ambulatory BP monitoring-derived salt sensitivity in a cohort of patients with uncontrolled hypertension on habitual salt intake. RDN was performed in 153 hypertensive patients, who were categorized into low intermediate and high-salt sensitivity groups, based on the ambulatory BP monitoring-derived salt sensitivity index estimated prior to (baseline) and at 3, 6 and 12 months after the procedure as previously described. Crude and adjusted mixed effects ordinal regression models were fitted to test for changes in the proportions of salt sensitivity risk during follow-up. The proportions of individuals in the intermediate and high-salt sensitivity risk group increased after RDN and the odds for being in a higher estimated salt sensitivity risk group at 3, 6 and 12 months follow-up compared with baseline were highly significant during the 12 months follow-up period. Increased salt sensitivity after RDN may represent a compensatory mechanism to maintain renal capacity for adequate salt handling. This novel finding may have implications for patient management after RDN, such as prescription of salt moderation to further optimize RDN-induced BP-lowering efficacy.

COVID-19 and renin angiotensin aldosterone system: Pathogenesis and therapy.

AimsThe severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) binds to the ACE2 component of the renin‐angiotensin aldosterone system (RAAS) and infects the human cells. The aims of the present review were to look at the role and alteration of the RAAS components in SARS‐CoV‐2 infection, therapeutic approaches, and clinical trials in this field.MethodsWe surveyed the literature (PubMed, Web of Science, and Scopus) till August 18, 2021, and 59 published papers regarding the components of the RAAS and their role and alterations in SARS‐CoV‐2 infection along with various COVID‐19 therapies based on the RASS components were included in the study.ResultsACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor inhibitors are agents that significantly enhance the ACE2 and Ang‐(1‐7) levels, which can be suggestive for their role as therapeutics against SARS‐CoV‐2 infection. Beta‐adrenergic blockers, which negatively regulate renin release from juxtaglomerular cells, and vitamin D, as a regulator of the RAAS and renin expression, are proposed therapeutics in the treatment of COVID‐19. Some antihyperglycemic agents could be potentially protective against COVID‐19‐induced lung injury. Also, the inhibition of the Janus kinase/signal transducer and activator of the transcription pathway as a potential treatment for COVID‐19 has been suggested. Finally, resveratrol, an antioxidant that can suppress Ang II, has been suggested as an adjunct to other therapies.ConclusionRegarding the suggested potential therapies for COVID‐19, there are many clinical trials whose results might change the treatment strategies of SARS‐CoV‐2 infection. So, the results of well‐organized clinical trials on the efficacy and safety of the mentioned agents in the treatment of COVID‐19 will be useful in the management and therapy of the disease.

Extracellular cAMP: The Past and Visiting the Future in cAMP-Enriched Extracellular Vesicles.

It is recently discovered that the cyclic nucleotide, cyclic adenosine monophosphate (cAMP) can be enriched in the extracellular vesicles (EVs) isolated from endothelial cells. In the current perspective a historical context for the discovery of the extracellular cAMP is provided. The story of extracellular cAMP through investigations addressing the molecule's role in the adenosine pathway is followed, which is widespread in mammalian physiology. The adenosine pathway mediates normal physiological conditions such as renin release, phosphate transport, etc., and participates in pathological conditions such as bronchoconstriction of the airways. Furthermore, adenosine mediated biological pathways are regulated via the receptor mediated intracellular cAMP pathway in mammalian cells. It then speculates on the question of whether cAMP enriched EVs could bypass typical receptor mediated cell signaling and directly activate cAMP signaling cascade in target cells. Preliminary studies to suggest cAMP enriched EVs are provided, added to naïve endothelial cells, results in an increase in intracellular cAMP. An alternate mechanism is proposed, apart from the traditional adenosine pathway, that extracellular cAMP may exert its effects and put into perspective how it might consider circulating cAMP moving forward.

Screening of QTc interval and global autonomic activity in autosomal dominant polycystic kidney disease and atherosclerotic renal artery stenosis hypertensive patients.

Arterial hypertension (AH) represents a major risk factor for cardiovascular disease and is associated to several complications, such as prolonged corrected QT (QTc) interval and impaired heart rate variability (HRV). Secondary causes of AH include autosomal dominant polycystic kidney disease (ADPKD) and atherosclerotic renal artery stenosis (ARAS), both known to be related to arrhythmic risk and autonomic imbalance. The aim of the study is to evaluate whether global autonomic activity and QTc interval differently affect ADPKD and ARAS hypertensive patients. An observational study was performed on 59 patients: 16 ADPKD patients and 19 diagnosed with ARAS, compared to 24 healthy controls (HC). All patients underwent clinical evaluation, biochemical lab tests, 24-hour electrocardiogram (ECG) and renal Doppler ultrasound. HRV was assessed through the analysis of 24-hour ECG to detect standard deviation of normal-to-normal RR intervals (SDNN). QTc interval was defined as prolonged when > 440 msec. SDNN was significantly lower in ADPKD and ARAS patients than HC (p < 0.0001) and no significant differences were found between ADPKD and ARAS patients (p > 0.05). QTc was found significantly higher in ARAS patients than HC (p = 0.001) and in ARAS patients than ADPKD patients (p = 0.004). The pathogenesis of hypertension in ADPKD and ARAS patients is related to the activation of the renin angiotensin aldosterone system (RAAS). In ADPKD, cyst enlargement leads to kidney ischemia and renin release, associated to endothelial dysfunction, low nitric oxide and sympathetic tone activation. Differently, reduction in renal perfusion pressure activates RAAS and renal adrenergic nerves in ARAS patients. We can speculate that prolonged QTc interval is more present in ARAS vs. ADPKD hypertensive patients due to a greater activation of RAAS. We suggest adding 24-hour HRV evaluation in association with traditional risk factors in course of ADPKD and ARAS hypertension to better stratify cardiovascular risk in these groups of patients.

Abstract MP67: Differential Effects Of Selective Renal Denervation On Intrarenal Neurohormone System Involved In Blood Pressure Regulation

Aims: To investigate alterations of intrarenal neurohormonal system involved in BP regulation after renal nerve stimulation (RNS)-guided renal denervation (RDN), and compare the significance of ablation on different BP-elevated magnitude sites. Methods and Results: Twenty-one dogs that met inclusion criteria were randomized to receive RDN at strong (SRA group, n=7) or weak (WRA group, n=7) BP-elevation response sites guided by RNS, or underwent RNS only (RNS-control, RSC, n=7), and fully recovered from the acute experiments. After 4 weeks, renal sympathetic and renin angiotensin system activity parameters, and major transporter expression were assessed by immunology and histochemistry. Compared with RSC group, RDN therapy significantly attenuated renal norepinephrine and tyrosine hydroxylase levels, alleviated renin release, and inhibited onsite generation of angiotensinogen. Meanwhile, the expression of exciting axis components, including angiotensin-converting enzyme (ACE), angiotensin II and angiotensin II type-1 receptor, were down-regulated, while the protective axis components such as ACE2 and Mas receptors, were up-regulated in both WRA and SRA group. Moreover, RDN reduced the abundance of aquaporin-1 and aquaporin-2 in kidneys. Although RDN had a minimal effect on overall NKCC2 expression, its activation (p-NKCC2) and directional enrichment in the apical membrane (mNKCC2) were dramatically blunted. Further analysis showed that all these changes were more significant in SRA group than WRA group. Conclusions: RDN effectively reduced systemic BP by affecting renal neurohormone-receptor axis, as well as expression and/or activation of major transporters. Selective RDN at strong BP-response sites presented a more superior beneficial effect, reconfirmed the feasibility of RNS-guided RDN.

Plasma renin and aldosterone concentrations related to endovascular ultrasound renal denervation in the RADIANCE-HTN SOLO trial.

The RADIANCE-HTN SOLO trial demonstrated a greater reduction in daytime ambulatory SBP at 2 months by endovascular ultrasound renal denervation than sham procedure. We hypothesized that plasma renin and aldosterone concentrations would be associated with the SBP response to renal denervation. Hypertensive patients were randomized to renal denervation (n = 74) or sham (n = 72) after a 4-week washout of antihypertensive medications. In a 53-patient subset, 2-month and 6-month plasma renin and aldosterone concentration were measured. Dietary sodium was not controlled. Mean age of the 29 treatment and 24 sham patients was 54 years; 62% were men; 17% black. Daytime ambulatory SBP fell in the denervation but not the sham group at 2 months (-7.8 ± 10.7 vs. -0.1 ± 10.1 mmHg; P = 0.048). Baseline plasma renin and aldosterone concentrations were in the low-normal range, did not change significantly at 2 months in either group and did not predict response to renal denervation. At 6 months, after the addition of antihypertensive medications, there was a significant rise in renin in the sham but not the denervation group. Although renal denervation but not sham resulted in a decrease in daytime ambulatory SBP at 2 months, renin and aldosterone concentrations did neither predict the BP response to renal denervation; nor did they fall after denervation. A rise in renin at 6 months in the sham group likely represents confounding from antihypertensive medications. Whether the BP-lowering effect of renal denervation depends on reducing local intrarenal renin release requires further study.

Cucumber and honey soaking reduces hypertension in the elderly

Hypertension is a condition of increasing a person's blood pressure beyond normal limits, causing increased morbidity and mortality. Hypertension can be reduced by consuming cucumber which contains potassium which inhibits the release of renin so that there is an increase in sodium and water excretion. In addition, it can also be reduced by consuming honey which can prevent the formation of plaque attached to the walls of blood vessels so that it can eliminate bad cholesterol for the body. This study aimed to determine the effect of giving cucumber and honey water immersion on Elderly Hypertension. This study used a Quasy Experimental design with a Pretest and Posttest with Control Group design. Sampling using a simple random sampling technique. The sample in this study amounted to 30 elderly people using the paired sample t-test statistical test. The results showed that the average blood pressure of the intervention group before being given the cucumber and honey water immersion was 153.6/84 mmHg and after it was 148.3/82.1 mmHg. The average blood pressure of the control group before being given the cucumber and honey water immersion was 158.5/80.2 mmHg and after it was 163.5/80.2 mmHg with p = 0.000. In the results of the independent sample test the intervention group before being given therapy, namely Sig. (2-tailed) = 0.027, the control group before treatment was Sig. (2-tailed) = 0.045. While the test results of the intervention group after being given therapy are Sig. (2-tailed) = 0.124, the control group after being given therapy is Sig. (2-tailed) = 0.139. There is an effect of giving cucumber and honey water immersion therapy on changes in blood pressure in the elderly with hypertension. But there is no difference in the average blood pressure of the Hypertensive Elderly. It is expected that the elderly with hypertension can make cucumber and honey water immersion as an alternative therapy to reduce hypertension

A Retinoic Acid β 2‐Receptor Agonist Exerts Cardioprotective Effects

Metabolic syndrome and hyperlipidemia are causally associated with myocardial ischemia and oxidative stress. We have now investigated the effects of AC261066, a synthetic selective agonist for the retinoic acid β2-receptor, in an ex vivo ischemia/reperfusion (I/R) injury model in hearts using genetically hypercholesterolemic (ApoE-/-) and metabolic syndrome inducing high fat diet (HFD) fed wild-type mouse models. We found that a 6-week oral treatment with AC261066 in both models exerts protective effects when their hearts are subsequently subjected to I/R ex vivo in the absence of AC261066. In ApoE-/- mice this cardioprotection ensued without hyperlipidemic changes. Cardioprotection consisted of attenuation of infarct size, diminution of norepinephrine (NE) spillover, and alleviation of reperfusion arrhythmias. This cardioprotection was associated with a reduction in oxidative stress and mast cell (MC) degranulation. We suggest that the reduction in myocardial injury and adrenergic activation, and the antiarrhythmic effects, result from decreased formation of oxygen radicals and toxic aldehydes that is known to elicit the release of MC-derived renin, promote the local renin-angiotensin system activation that enhances NE release, and reperfusion arrhythmias. Because these beneficial effects of AC261066 occurred at the ex vivo level following oral drug treatment, our data suggest that AC261066 could be viewed as a therapeutic means to reduce I/R injury of the heart, and potentially also be considered in the treatment of other cardiovascular ailments such as chronic arrhythmias and cardiac failure. Currently we are exploring the cardiac protective effects of AC261066 using an in vivo heart failure model.

POS-413 MANAGEMENT OF HYPERTENSION AFTER RENAL SYMPATHETIC DENERVATION IN MALE PATIENTS

Renal sympathetic denervation (RSD) is a catheter-based medical procedure that uses radiofrequency ablation on the renal sympathetic nerves to attenuate cardiac pulse pressure as well as juxtaglomerular renin release through beta-1 adrenergic receptor stimulation. Early studies on RSD demonstrated a marked benefit in the patients who underwent the procedure, but early cases have left more to be desired due to heterogeneity of clinical trial designs. Currently, the International Consensus Statement on Renal Denervation reports the need for further evaluation of RSD efficacy and suggested that RDN should not be offered to patients outside of clinical trials. Despite the International Consensus Statement recommendations, there are a number of reported peer-reviewed case reports of hypertensive patients undergoing renal denervation, yet there is currently no literature or systematic review on these case reports determining if the patient outcomes have produced similar results to the current literature of RSD clinical trials. Therefore, the aim of this study is to evaluate the efficacy of RSD treatment in attenuating hypertension among patients. A systematic review of the literature was performed on MEDLINE, Google Scholar, and the Cochrane Database of Systematic Reviews for renal denervation case studies. This study methodology was registered by PROSPERO International prospective register of systematic reviews (National Institute for Health Research). The search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist. Twenty-four male patients were found to be undergoing renal sympathetic denervation for hypertension treatment. The mean age of the patient population was 48.75 (CI: 41.68 - 55.82). The mean body mass index (BMI) was 31.02 (CI: 24.69 - 37.34). The reported duration of an ablation varied among each study, noting the shortest duration at 10 seconds, and the longest duration at 120 seconds. At post-RSD treatment, the mean 24-hour post-operative systolic blood pressure of reported cases was 144.40 mmHg (CI: 114.03 - 174.77). At 1-month follow-up, the mean systolic blood pressure was 142.00 mmHg (CI: 117.91 - 166.10). At 3-month follow-up, mean systolic blood pressure decreased to 126.25 mmHg (CI: 117.21 - 135.29). At 6-month follow-up, the mean systolic blood pressure increased to 160.00 mmHg. At 1-year follow-up, the mean systolic blood pressure of reported cases decreased to 131.00 mmHg. After RSD treatment, patient follow-up histories reported a mean number of 3.00 antihypertensive medications (CI: 1.96 - 4.04). On average, the severity of hypertension declined from borderline-malignant hypertension to stage I hypertension. The resulting reduction in blood pressure during these follow-up visits is consistent with the results of larger renal denervation registry studies, which addresses the International Consensus Statement’s desire for further evidence. However, one of the concerns posed in the literature regarding renal sympathetic denervation was the lack of reliable improvements in blood pressure over a prolonged period of time. Areas of interest that merit further study include tracking blood pressure changes beyond one year, monitoring for complications, and following changes in all-cause mortality.

Function of Renal Nerves in Kidney Physiology and Pathophysiology.

Renal sympathetic (efferent) nerves play an important role in the regulation of renal function, including glomerular filtration, sodium reabsorption, and renin release. The kidney is also innervated by sensory (afferent) nerves that relay information to the brain to modulate sympathetic outflow. Hypertension and other cardiometabolic diseases are linked to overactivity of renal sympathetic and sensory nerves, but our mechanistic understanding of these relationships is limited. Clinical trials of catheter-based renal nerve ablation to treat hypertension have yielded promising results. Therefore, a greater understanding of how renal nerves control the kidney under physiological and pathophysiological conditions is needed. In this review, we provide an overview of the current knowledge of the anatomy of efferent and afferent renal nerves and their functions in normal and pathophysiological conditions. We also suggest further avenues of research for development of novel therapies targeting the renal nerves.