Activation Of Renin-angiotensin System Research Articles

Genetic Variations in Angiotensinogen Gene and Risk of Preeclampsia: A Pilot Study

Preeclampsia (PE) is a typical hypertensive disorders of pregnancy (HDP) which can cause substantial morbidity and mortality in both pregnant women and fetuses. The renin-angiotensin system (RAS) genes are the main HDP-causing genes, and Angiotensinogen (AGT) as the initial substrate can directly reflect the activity of the entire RAS. However, the association between AGT SNPs and PE risk has rarely been confirmed. This study was carried out to determine whether AGT SNPs could affect the risk of PE in 228 cases and 358 controls. The genotyping result revealed that the AGT rs7079 TT carrier was related to increased PE risk. Further stratified analysis illustrated that the rs7079 TT genotype significantly increased the PE risk in subgroups of Age < 35, BMI < 25, Albumin (ALB) ≥ 30 and Aspartate aminotransferase (AST) < 30. These findings demonstrated that the rs7079 might be a promising candidate SNP strongly associated with PE susceptibility.

Reduction of anaerobic glycolysis contributes to angiotensin II-induced podocyte injury with foot process effacement

Activation of the renin-angiotensin system is associated with podocyte injury and has been well demonstrated as a pivotal factor in the progression of chronic kidney disease. Podocyte energy metabolism is crucial for maintaining their physiological functions. However, whether renin-angiotensin system activation promotes chronic kidney disease progression by disturbing the energy metabolism of podocytes has not been elucidated. Angiotensin II, the main active molecule of the renin-angiotensin system, plays a crucial role in chronic kidney disease initiation and progression, but its impact on podocyte metabolism remains unclear. Here, we demonstrate a rapid decrease in the expression of pyruvate kinase M2, a key glycolytic enzyme, and reduced glycolytic flux in podocytes exposed to angiotensin II invivo and invitro. Podocyte-specific deletion of pyruvate kinase M2 in mice aggravated angiotensin II-induced glomerular and podocyte injury with foot process effacement and proteinuria. The inhibition of glycolysis was accompanied by adenosine triphosphate deficiency, cytoskeletal remodeling and podocyte apoptosis. Mechanistically, we found that angiotensin II-induced glycolysis impairment contributed to an insufficient energy supply to the foot process, leading to podocyte injury. Additionally, pyruvate kinase M2 expression was found to be reduced in podocytes from kidney biopsies of patients with hypertensive nephropathy and diabetic kidney disease. Thus, our findings suggest that glycolysis activation is a potential therapeutic strategy for podocyte injury.

Renin-angiotensin system: The underlying mechanisms and promising therapeutical target for depression and anxiety.

Emotional disorders, including depression and anxiety, contribute considerably to morbidity across the world. Depression is a serious condition and is projected to be the top contributor to the global burden of disease by 2030. The role of the renin-angiotensin system (RAS) in hypertension and emotional disorders is well established. Evidence points to an association between elevated RAS activity and depression and anxiety, partly through the induction of neuroinflammation, stress, and oxidative stress. Therefore, blocking the RAS provides a theoretical basis for future treatment of anxiety and depression. The evidence for the positive effects of RAS blockers on depression and anxiety is reviewed, aiming to provide a promising target for novel anxiolytic and antidepressant medications and/or for improving the efficacy of currently available medications used for the treatment of anxiety and depression, which independent of blood pressure management.

The systemic and hepatic alternative renin–angiotensin system is activated in liver cirrhosis, linked to endothelial dysfunction and inflammation

We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography–tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1–7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1–5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1–7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1–7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation.

S-23-1: OCCUPATIONAL AND ENVIRONMENTAL INFLUENCES ON HYPERTENSION

In this brief review I shall try to discuss several topics related to hypertension which maybe associated with occupational and environmental effects. Effects of dietary sodium will not be discussed as these are extensively discussed elsewhere. Occupational stress is difficult to define but there seems to be a relationship between high demands and relatively low control, and blood pressure in both men and women despite different professional distribution. Noise, a relatively less recognized stressor that may be associated with hypertension Both industrial noise and urban noise. Recently due to the Covid19 lockdown and reduction of aircraft noise in relevant areas a reduction of blood-pressure was noted. Seasonal variation with rise of blood pressure during cold and perhaps shorter daytime light seasons, and subsequent reduction in the summer with its higher temperatures and longer light hours is one environmental factor. Air pollution, especially that associated with high level small particulate matter equal to, or smaller than 0.25 μm, was associated with hypertension in several studies, with quite and ethnic and geographic variability. High altitude exposure (higher than 2500 m), involves hypoxemia (in addition to radiation, cold temperatures, and dehydration because of dryness of inhaled air), resulting in renin angiotensin system activation and sympathetically induced vascular contraction, and elevation of pulse rate and blood-pressure at rest and an exaggerated increase during exercise. Immigration seems to be associated with hypertension through different mechanisms in different populations. Mechanisms of these effects are not well understood though some must be mediated through sympathetic activation, others through the renin angiotensin system though, hypoxemia, altered redox state and inflammation all might participate along with other mechanisms

PS-B12-7: PERSISTENT REDUCTION IN RENAL RENIN FOLLOWING EARLY TREATMENT OF SPONTANEOUSLY HYPERTENSIVE RATS WITH LOSARTAN

Objective: Abnormalities of renin-angiotensin system (RAS) and renal function have been reported in young spontaneously hypertensive rats (SHR) and blood pressure (BP) can be permanently reset to lower levels after brief early treatment with RAS inhibitors. We sought to determine whether renal renin was affected long-term by early RAS blockade. Design: Male SHR were treated via minipump from 10–14 weeks of age with vehicle (Veh, n = 12) or losartan (Los, n = 14, 7.5 mg/kg/d). Four Veh and six Los SHR were culled at 14-weeks and the remaining animals at 20-weeks. To control for effects of low BP another group received hydralazine (HZ, n = 6, 1 mg/kg/d) from 10–20 weeks. Methods: At 14- and 20-weeks systolic BP was measured, and kidneys collected. Three micrometer paraffin sections of renal cortices were counterstained with hematoxylin for renin immunolabelling, assessed for each animal as the percentage of labelling in 200 glomeruli which displayed the afferent arteriole entering the glomerulus. Results: At 14-weeks the systolic BP (mean ± SEM) was significantly (P &lt; 0.001 by ANOVA) lower in both the Los (145 ± 7 mmHg) and HZ (153 ± 7 mmHg) SHR compared with Veh (206 ± 6 mmHg). At 20-weeks, the same pattern persisted (Los: 187 ± 6 mmHg; HZ: (155 ± 4 mmHg; Veh: 220 ± 6 mmHg) (P &lt; 0.001 by ANOVA). Renal renin immunolabelling increased dramatically during treatment at 14-weeks (44.8 ± 1.1%) compared with Veh (10.5 ± 1.7%) (P &lt; 0.0001 by ANOVA). However, at 20-weeks renal renin was significantly lower in Los (7.7 ± 0.9%) (P &lt; 0.05 by ANOVA) compared with Veh (11.9 ± 1.2%), while renal renin was significantly higher in HZ kidneys (18.0 ± 1.0%) than both Los and Veh kidneys (P &lt; 0.01 by ANOVA). Conclusions: The persistently low BP in SHR following brief early treatment with losartan is associated with reduced renal renin. Normally one would expect activation of the renal RAS with lower BP, as observed with the hydralazine-treated SHR. These results suggest that long-term reduction in renal renin following brief early RAS blockade in SHR might cause the persistently reduced BP seen in these animals.

PS-BPB08-1: ANGIOTENSIN II AT1A RECEPTORS IN THE PROXIMAL TUBULES PLAY A CRITICAL ROLE IN THE DEVELOPMENT OF TWO-KIDNEY, ONE-CLIP GOLDBLATT HYPERTENSION

Objective: It is well recognized that the activation of the renin-angiotensin system (RAS) in the clipped kidney plays a critical role in the development of two-kidney, one-clip Goldblatt hypertension (2K1C) in animal models, but the roles of intratubular angiotensin II (Ang II) AT1 (AT1a) receptors and its downstream target, Na+/H+ exchanger 3 (NHE3) in the proximal tubules have not been determined previously. In the present study, we tested the hypothesis that genetic deletion of AT1a receptors selectively in the proximal tubules of the kidney attenuates the development of 2K1C Goldblatt hypertension via AT1a receptor-mediated, Na+/H+ exchanger 3 (NHE3)-dependent mechanisms. Design and Methods: To test the hypothesis, 2K1C Goldblatt hypertension was induced by placing a silver clip, 0.12 mm internal diameter, on the left renal artery for 4 weeks in adult male and female wild-type (WT), global AT1areceptor knockout (Agtr1a-/- ), proximal tubule (PT)-specific Agtr1a-/- (PT-Agtr1a-/- ), or PT-Nhe3-/- mice, respectively. Results: Systolic blood pressure increased in a time-dependent manner reaching a maximal response by Week 2–3 in wild-type mice (Basal: 112 ± 2 vs. 2K1C: 149 ± 4 mmHg, n = 12, P &lt; 0.01). 2K1C Goldblatt hypertension in WT mice was associated with significant increases in renin mRNA expression in the clipped kidney (Control: 2066 ± 255 vs. Clipped: 3144 ± 569 copies/ng RNA, P &lt; 0.01), and decreases in renin mRNA expression in the nonclipped right kidney (1738 ± 341 copies/ng RNA, P &lt; 0.05). Plasma Ang II levels were significantly increased in WT mice with 2K1C Goldblatt hypertension (Control: 50.2 ± 7.2 vs. 2K1C: 109.7 ± 17.2 pg/ml, P &lt; 0.05). Glomerular and tubulointerstitial fibrotic responses were also significantly increased in the clipped kidney (P &lt; 0.01). In contrast to WT mice, the development of 2K1C hypertension was completely attenuated in global Agtr1a-/- (Basal: 88 ± 4 vs. 2K1C: 92 ± 2 mmHg, n = 9, n.s.), PT-Agtr1a-/- mice (Basal: 101 ± 2 vs. 2K1C: 104 ± 4 mmHg, n = 12, n.s.), or PT-Nhe3-/- mice (Basal: 103 ± 3 vs. 109 ± 5 mmHg, n.s.). Renin mRNA expression was not different in clipped and nonclipped kidney of Agtr1a-/- mice, but it was decreased in the nonclipped kidney of PT-Agtr1a-/- mice (P &lt; 0.05). Conclusions: Taken together, our results suggest that the activation of intratubular RAS in the proximal tubules and increase of NHE3-mediated proximal tubular Na+ reabsorption play a key role in the development of 2K1C Goldblatt hypertension in mice.

PS-B08-10: COMBINATION OF SYSTEMIC ATRAP DEFICIENCY WITH ANGIOTENSIN II STIMULATION ACCELERATES THE DEVELOPMENT OF DIABETIC NEPHROPATHY IN STREPTOZOTOCIN TREATED MICE

Objective: One of the obstacles toward understanding the pathophysiology of diabetic nephropathy (DN) has been the lack of reliable animal models that faithfully replicate features of human DN. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R from the cell surface into the cytoplasm, resulting in the suppression of AT1R signaling pathway. We have recently reported that systemic ATRAP deficiency exaggerates streptozotocin (STZ)-induced DN via an activation of renal renin-angiotensin system (RAS) (Haruhara K, et al. Kidney Int 2022). However, STZ-induced diabetic ATRAP knockout mice still exhibited a modest increase in albuminuria with limited pathological changes just in glomerulus. To establish more robust DN models, we examined the effect of Ang II stimulation on the development of DN in STZ-treated ATRAP knockout mice. Design and method: Male eight weeks old C57BL/6 mice (Ctrl) and systemic ATRAP-knockout mice (KO) were divided into three groups: 1) Ctrl-STZ, 2) Ctrl-STZ-Ang II, and 3) KO-STZ-Ang II. Hyperglycemia was induced by intraperitoneal injection of 55 mg/kg STZ for consecutive 5 days. From 4 weeks after STZ administration, Ang II (1000 ng/kg/min) was continuously administered by osmotic mini-pumps for 6 weeks. During the experimental period, body weights and levels of blood glucose were measured every 2 weeks. At 6 and 10 weeks after STZ administration, 24-hour urine samples were collected in metabolic cages, and urinary albumin excretion (UAE) was evaluated by ELISA. At the end of experimental period, mice were euthanized to evaluate renal pathological changes. Results: During the experimental period, body weight gain and levels of blood glucose were not significantly different between the three groups. Nonetheless, although levels of UAE at 6 weeks after STZ administration were still modest and comparable between the three groups, levels of UAE only in the KO-STZ-Ang II group were remarkably increased compared to those in the Ctrl-STZ and Ctrl-STZ-Ang II groups at 10 weeks after STZ administration (679.1 ± 583.7 vs 69.9 ± 10.0 vs 61.3 ± 8.2 μg/day, respectively). Furthermore, in the KO-STZ-Ang II group, exacerbation of mesangial expansion and interstitial fibrosis was observed. Conclusions: In STZ-induced diabetic mice, combination of systemic ATRAP deficiency with Ang II stimulation accelerated the development of DN, suggesting a potential to become a promising mouse model replicating key features of human DN.

PS-BPB08-4: IMPAIRED TCA CYCLE METABOLISM IN DIABETIC NEPHROPATHY IS LINKED TO ALBUMINURIA AND KIDNEY INJURY

Objective: Recent work has highlighted potential contributions of impaired renal energy metabolism, including mitochondrial dysfunction and altered fatty acid metabolism, in chronic kidney diseases including diabetic nephropathy (DN). However, causal connections between specific metabolic abnormalities and pathophysiology of DN have been difficult to establish. Here, we approach this question using a mouse model recapitulating characteristic features of human DN and a targeted metabolomics platform designed to assess key metabolic pathways involving amino acids, fatty acids, glycolysis and the TCA cycle. Design and method: We generated a mouse model of DN with underlying activation of the renin-angiotensin system (RAS) by a renin transgene (R) driven by the albumin promoter on the Akita background of type I diabetes (A). We have shown that on a susceptible 129/Sv background, Akita-ReninTg (AR) mice exhibit cardinal characteristics of human DN including high-grade albuminuria and glomerulosclerosis, whereas AR mice on a C57BL/6 background do not develop DN. To assess the impact of genetic background on energy metabolism in DN, kidneys from 24-week-old male AR mice on both backgrounds were evaluated by the targeted metabolome analysis. To further distinguish the impact of RAS activation on relevant pathways associated with kidney disease development, 12-week-old male 129/Sv AR mice were treated with the angiotensin receptor blocker (ARB) losartan 10 mg/kg/day for 12 weeks. 24-hour urine samples were collected in metabolic cages and urine albumin levels were measured by EIA. Kidneys from age-matched parental 129/Sv and C57BL/6 wild-type mice were analyzed as controls. Results: A distinct metabolic profile was observed in kidneys of DN-susceptible 129/Sv AR mice including reduced levels of C2 acetyl-carnitine that reflect a deficiency in acetyl-CoA, perturbations of TCA cycle intermediates and increased lactate levels. In addition, levels of phosphorylated-AMPK were reduced. These metabolic changes were absent in DN-resistant C57BL/6 AR mice. Treatment of 129/Sv AR mice with the ARB dramatically reduced albuminuria (906 ± 169 vs 193 ± 42 μg/day, p &lt; 0.01) and attenuated kidney pathology while restoring levels of C2 acetyl-carnitine, TCA intermediates, lactate and phosphorylated-AMPK toward normal. ARB treatment also increased kidney ATP content. In 129/Sv mice, there were statistically significant correlations between albuminuria and kidney levels of lactate, acetyl-carnitine, citrate and succinate. Conclusions: Thus, there is a distinct profile of impaired energy metabolism associated with DN susceptibility that is attenuated by RAS blockade. Impaired TCA cycle function and coincident increases in lactate are linked to albuminuria in mice with DN, and may contribute to kidney injury.

JS-HR-12: BASIC RESEARCH: ELUCIDATION OF “MOSAIC” PATHOGENESIS OF HYPERTENSION

Basic research plays critical roles in elucidating the “mosaic” pathogenesis of hypertension and developing its treatment. In the field of brain and autonomic nervous system, Chen et al. demonstrated that mild cold exposure elicits autonomic dysregulation, such as increased sympathetic activity and decreased baroreflex sensitivity, and poor sleep quality, causing blood pressure (BP) elevation in normotensive rats. This finding may have critical implications for the cardiovascular event occurrence with low ambient temperature. Domingos-Souza et al. showed that the ability of baroreflex activation to modulate hemodynamics and induce lasting vascular adaptation is critically dependent on the electrical parameters and duration of carotid sinus stimulation in spontaneously hypertensive rats (SHRs), proposing a rationale for improving baroreflex activation therapy in humans. In the kidney, Kasacka et al. showed that activity of Wnt/β-catenin pathway is increased in SHRs and 2K1C hypertensive rats, while it is inhibited in DOCA-salt rats. Intrarenal renin-angiotensin system (RAS) is involved in BP regulation. In renal damage with an impaired glomerular filtration barrier, liver-derived angiotensinogen filtered through damaged glomeruli regulates intrarenal RAS activity. Matsuyama et al. further showed that the glomerular filtration of liver-derived angiotensinogen depending on glomerular capillary pressure causes circadian rhythm of the intrarenal RAS. Otsuki et al. revealed that TWIST1, a transcription factor regulating mesodermal embryogenesis, transcriptionally upregulates complement 3, which has been demonstrated to activate intrarenal RAS, in the glomerular mesangial cells from SHRs. The RAS in the vascular system also contributes to BP regulation. Soring nexins (SNXs) are cellular sorting proteins and can regulate the expression and function of G protein-coupled receptors (GPCRs). Liu C et al. demonstrated that SNX1 knockout mice exhibit hypertension through vasoconstriction mediated by increased expression of GPCR AT1R within the arteries. Liu X et al. found that sirtuin 6 (SIRT6) expression is downregulated in the aortae of aged rats and showed that SIRT6 knockdown enhances angiotensin II-induced vascular adventitial aging by activating NF-κB pathway in vitro studies. The studies investigating extracellular vesicles (EVs) and gut microbiota have been increased. Ochiai-Homma et al. showed that pendrin in urinary EVs can be a useful biomarker for diagnosis and treatment of primary aldosteronism. Wu et al. demonstrated that captopril has the potential to rebalance the dysbiotic gut microbiota of DOCA-salt hypertensive rats. Several reports indicate the potential treatment for hypertension and the associated organ damages: rivaroxaban in cardiac hypertrophy; nebivolol, maximakinin, and Pinggan-Qianyang in hypertension; and melatonin and crocin in gestational hypertension.

JS-ECCR/HBPRCA-4: NEURAL CONTROL OF CARDIOVASCULAR FUNCTION AND ERYTHROPOIESIS BY THE BRAIN RAS

The renin-angiotensin system (RAS) strongly modulates not only cardiovascular homeostasis but also other non-cardiovascular physiological processes like erythropoiesis. The production of the peptide hormone angiotensin II (Ang II) in the circulatory system constitutes the main source of the RAS activity. However, Ang II has also been recognized to be generated locally by various tissues, because RAS components are either locally expressed and/or imported from the circulation. Contrary to peripheral organs, the blood-brain-barrier limits the traffic of all circulating RAS proteins into the brain, thus, brain Ang II formation relies exclusively on locally expressed RAS precursor and enzymes. Several brain cardiovascular centers contain neuronal populations responsive to Ang II that take part in sympathetic nerve outflow, vasopressin secretion, thirst and salt appetite. Angiotensinogen (Agt), the RAS precursor, is mostly produced by astrocytes in the brain. To investigate the role of the brain RAS in cardiovascular control and erythropoiesis, two transgenic rodent models with astrocyte-specific Agt gain- and loss-of-function were phenotyped. In both models, astrocyte-specific transgene expression was delivered using the human GFAP promoter. The gain-of-function model is a transgenic mouse overexpressing rat Agt, and the loss-of-function model is a rat expressing an antisense RNA against the endogenous Agt mRNA. The transgenic mouse line overexpresses the rat Agt mRNA distributed across the brain, including areas containing cardiovascular centers. Overexpression of Agt increased brain Ang II formation but reduced the peripheral Ang II levels. Rats expressing the antisense RNA exhibited a brain-specific decrease of Agt protein by ∼90%. The cardiovascular phenotyping of the two lines demonstrated opposing effects for the brain RAS. Increased brain RAS reactivity was associated with high BP, vascular sympathetic tone and vasopressin secretion, and downregulation of the brain RAS reduced BP and vasopressin secretion. Similarly, the brain RAS modulated erythropoiesis in contrary directions because capillary hematocrit experiments revealed that overproduction of Ang II in the brain correlates with increased erythropoiesis while reduced Ang II production with moderated erythropoiesis. These findings were further validated using detailed blood cell counting with an automated hematology analyzer. Submitting the transgenic mice with increased brain Ang II and respective controls to peripheral sympathectomy with 6-hydroxydopamine revealed that brain Ang II via sympathetic nerve activity increases erythropoiesis in transgenic mice. Altogether, these models confirmed the functionality of the brain RAS, and that baseline BP and erythropoiesis depends on its integrity and reactivity.

Sodium-glucose cotransporter inhibitors and kidney fibrosis: review of the current evidence and related mechanisms.

Sodium-glucose cotransporter inhibitors (SGLT2i) are a new class of anti-diabetic drugs that have beneficial cardiovascular and renal effects. These drugs decrease proximal tubular glucose reabsorption and decrease blood glucose levels as a main anti-diabetic action. Furthermore, SGLT2i decreases glomerular hyperfiltration by a tubuloglomerular feedback mechanism. However, the renal benefits of these agents are independent of glucose-lowering and hemodynamic factors, and SGLT2i also impacts the kidney structure including kidney fibrosis. Renal fibrosis is a common pathway and pathological marker of virtually every type of chronic kidney disease (CKD), and amelioration of renal fibrosis is of utmost importance to reduce the progression of CKD. Recent studies have shown that SGLT2i impact many cellular processes including inflammation, hypoxia, oxidative stress, metabolic functions, and renin-angiotensin system (RAS) which all are related with kidney fibrosis. Indeed, most but not all studies showed that renal fibrosis was ameliorated by SGLT2i through the reduction of inflammation, hypoxia, oxidative stress, and RAS activation. In addition, less known effects on SGLT2i on klotho expression, capillary rarefaction, signal transducer and activator of transcription signaling and peptidylprolyl cis/trans isomerase (Pin1) levels may partly explain the anti-fibrotic effects of SGLT2i in kidneys. It is important to remember that some studies have not shown any beneficial effects of SGLT2i on kidney fibrosis. Given this background, in the current review, we have summarized the studies and pathophysiologic aspects of SGL2 inhibition on renal fibrosis in various CKD models and tried to explain the potential reasons for contrasting findings.

AT1 receptor autoantibodies mediate effects of metabolic syndrome on dopaminergic vulnerability

The metabolic syndrome has been associated to chronic peripheral inflammation and related with neuroinflammation and neurodegeneration, including Parkinson’s disease. However, the responsible mechanisms are unclear. Previous studies have involved the brain renin-angiotensin system in progression of Parkinson’s disease and the angiotensin receptor type 1 (AT1) has been recently revealed as a major marker of dopaminergic vulnerability in humans. Dysregulation of tissue renin-angiotensin system is a key common mechanism for all major components of metabolic syndrome. Circulating AT1 agonistic autoantibodies have been observed in several inflammation-related peripheral processes, and activation of AT1 receptors of endothelial cells, dopaminergic neurons and glial cells have been observed to disrupt endothelial blood -brain barrier and induce neurodegeneration, respectively. Using a rat model, we observed that metabolic syndrome induces overactivity of nigral pro-inflammatory renin-angiotensin system axis, leading to increase in oxidative stress and neuroinflammation and enhancing dopaminergic neurodegeneration, which was inhibited by treatment with AT1 receptor blockers (ARBs). In rats, metabolic syndrome induced the increase in circulating levels of LIGHT and other major pro-inflammatory cytokines, and 27-hydroxycholesterol. Furthermore, the rats showed a significant increase in serum levels of proinflammatory AT1 and angiotensin converting enzyme 2 (ACE2) autoantibodies, which correlated with levels of several metabolic syndrome parameters. We also found AT1 and ACE2 autoantibodies in the CSF of these rats. Effects of circulating autoantibodies were confirmed by chronic infusion of AT1 autoantibodies, which induced blood–brain barrier disruption, an increase in the pro-inflammatory renin-angiotensin system activity in the substantia nigra and a significant enhancement in dopaminergic neuron death in two different rat models of Parkinson’s disease. Observations in the rat models, were analyzed in a cohort of parkinsonian and non-parkinsonian patients with or without metabolic syndrome. Non-parkinsonian patients with metabolic syndrome showed significantly higher levels of AT1 autoantibodies than non-parkinsonian patients without metabolic syndrome. However, there was no significant difference between parkinsonian patients with metabolic syndrome or without metabolic syndrome, which showed higher levels of AT1 autoantibodies than non-parkinsonian controls. This is consistent with our recent studies, showing significant increase of AT1 and ACE2 autoantibodies in parkinsonian patients, which was related to dopaminergic degeneration and neuroinflammation. Altogether may lead to a vicious circle enhancing the progression of the disease that may be inhibited by strategies against production of these autoantibodies or AT1 receptor blockers (ARBs).

689 IMPACT OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS ON CLINICAL OUTCOME IN HYPERTENSIVE PATIENTS WITH SEVERE AORTIC STENOSIS UNDERGOING TRANSCATHETER AORTIC VALVE IMPLANTATION: INSIGHT FROM THE EFFECTAVI REGISTRY

Abstract Aims Left ventricular pressure overload is connected with cardiac renin–angiotensin system activation, which may lead to myocardial fibrosis and poorer clinical outcomes. Hypertensive patients with symptomatic, severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) in the EffecTAVI registry were evaluated for the association between baseline treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and clinical outcomes. Methods and results The research comprised 373 patients with moderate, high, or prohibitive risk who had TAVI in the EffecTAVI registry (NCT05235555). Using Kaplan–Meier event rates and study-stratified multivariable Cox proportional hazards regression models, we evaluated clinical outcomes at 2 years according to ACEi/ARB therapy status at baseline. Among the 327 patients with hypertension included in the present study, 222 (67.9%) were treated with ACEI/ARB at baseline, whereas 105 (32.1%) were not. Treatment with ACEI/ARB was related with decreased all-cause mortality (HR=0.46, 95% CI 0.25-0.90, p=0.011), although this association was not statistically significant after multivariable adjustment for important covariates. Analyzing pre-procedural ACEi and ARBs separately, ARBs administration was related with a 58% decrease in all-cause mortality (HR=0.42, 95% CI 0.18-0.98, p=0.04), which was confirmed in multivariate analysis. Conclusion In a small cohort of hypertensive patients with severe symptomatic AS from the EffecTAVI registry, ARBs treatment at baseline was independently associated with a lower risk of 2-year all-cause mortality.

TSPAN12 (Tetraspanin 12) Is a Novel Negative Regulator of Aldosterone Production in Adrenal Physiology and Aldosterone-Producing Adenomas.

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism, a condition of low-renin hypertension, in which aldosterone overproduction is usually driven by a somatic activating mutation in an ion pump or channel. TSPAN12 is differentially expressed in different subgroups of APAs suggesting a role in APA pathophysiology. Our objective was to determine the function of TSPAN12 (tetraspanin 12) in adrenal physiology and pathophysiology. APA specimens, pig adrenals under dietary sodium modulation, and a human adrenocortical cell line HAC15 were used for functional characterization of TSPAN12 in vivo and in vitro. Gene ontology analysis of 21 APA transcriptomes dichotomized according to high versus low TSPAN12 transcript levels highlighted a function for TSPAN12 related to the renin-angiotensin system. TSPAN12 expression levels in a cohort of 30 APAs were inversely correlated with baseline plasma aldosterone concentrations (R=-0.47; P=0.009). In a pig model of renin-angiotensin system activation by dietary salt restriction, TSPAN12 mRNA levels and TSPAN12 immunostaining were markedly increased in the zona glomerulosa layer of the adrenal cortex. In vitro stimulation of human adrenocortical human adrenocortical cells with 10 nM angiotensin II for 6 hours caused a 1.6-fold±0.13 increase in TSPAN12 expression, which was ablated by 10 μM nifedipine (P=0.0097) or 30 μM W-7 (P=0.0022). Gene silencing of TSPAN12 in human adrenocortical cells demonstrated its inverse effect on aldosterone secretion under basal and angiotensin II stimulated conditions. Our findings show that TSPAN12 is a negative regulator of aldosterone production and could contribute to aldosterone overproduction in primary aldosteronism.

Heme oxygenase-1 protects against PM2.5 induced endothelial dysfunction through inhibition of HIF1α

PM2.5 has been accepted as a strong risk factor for cardiovascular diseases. Activation of the renin-angiotensin system (RAS) has been proved to be a key factor in triggering vascular endothelial dysfunction upon PM2.5 exposure in our previous reports. In the current study, we observed the concurrent induction of hemoxygenase (HO)− 1 and RAS components (ANGII and AT1R) expression both in the vascular endothelial cell lines and in rat lung tissue after PM2.5 exposure. Furthermore, HO-1 inhibited RAS activation by suppressing the expression and activity of HIF1α, the upstream transcriptional activator of ANGII and AT1R. In addition, HO-1 blocked significantly increased the release of cell adhesion molecules and chemokines (VCAM-1, E-Selectin, P-Selectin, IL-8, MCP-1) that drive monocyte-endothelium adhesion, along with the enhanced the generation of oxidative stress response mediators in the vascular endothelium. These data together indicate that PM2.5 induced HO-1 upregulation functions as a self-defense response to antagonize endothelial dysfunction by inhibiting HIF1α-mediated RAS activation. Targeting endogenous protective pathway might be helpful to protect from PM2.5-induced cardiovascular injury.

Angiotensin-(1-9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway.

Endothelial apoptosis caused by activation of renin-angiotensin system (RAS) plays a vital part in the occurrence and progress of hypertension. Angiotensin-(1-9) (Ang-(1-9)) is a peptide of the counter-regulatory non-classical RAS with anti-hypertensive effects in vascular endothelial cells (ECs). However, the mechanism of action remains unclear. Considering that the endothelial apoptosis wascloselyrelatedto endoplasmic reticulum stress (ERS) and mitochondrial function. Herein, we aimed to elucidate the effects of Ang-(1-9) on endothelial apoptosis and the underlying molecular mechanism in angiotensin II (Ang II) induced hypertension. In human umbilical vascular endothelial cells (HUVECs), we observed Ang-(1-9) inhibited Ang II-induced ERS associated endothelial apoptosis. Mechanically, Ang-(1-9) inhibited endothelial apoptosis by blocking CNPY2/PERK mediated CaMKII/Drp1-dependent mitochondrial fission and eIF2α/CHOP signal. Consistent with above effects in HUVECs, in Ang II-induced hypertensive mice, we found administration of exogenous Ang-(1-9) attenuated endothelial apoptosis and arterial blood pressure, which were mediated by CNPY2/PERK signaling pathway. Our study indicated Ang-(1-9) inhibited Ang II-induced hypertension through CNPY2/PERK pathway. These findings may provide new insights for prevention and treatment of hypertension in future.

The systemic renin-angiotensin system in COVID-19

SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the “alternative” (alt) renin-angiotensin system (RAS). ACE2 counteracts angiotensin II by converting it to potentially protective angiotensin 1–7. Using mass spectrometry, we assessed key metabolites of the classical RAS (angiotensins I–II) and alt-RAS (angiotensins 1–7 and 1–5) pathways as well as ACE and ACE2 concentrations in 159 patients hospitalized with COVID-19, stratified by disease severity (severe, n = 76; non-severe: n = 83). Plasma renin activity (PRA-S) was calculated as the sum of RAS metabolites. We estimated ACE activity using the angiotensin II:I ratio (ACE-S) and estimated systemic alt-RAS activation using the ratio of alt-RAS axis metabolites to PRA-S (ALT-S). We applied mixed linear models to assess how PRA-S and ACE/ACE2 concentrations affected ALT-S, ACE-S, and angiotensins II and 1-7. Median angiotensin I and II levels were higher with severe versus non-severe COVID-19 (angiotensin I: 86 versus 30 pmol/L, p < 0.01; angiotensin II: 114 versus 58 pmol/L, p < 0.05), demonstrating activation of classical RAS. The difference disappeared with analysis limited to patients not taking a RAS inhibitor (angiotensin I: 40 versus 31 pmol/L, p = 0.251; angiotensin II: 76 versus 99 pmol/L, p = 0.833). ALT-S in severe COVID-19 increased with time (days 1–6: 0.12; days 11–16: 0.22) and correlated with ACE2 concentration (r = 0.831). ACE-S was lower in severe versus non-severe COVID-19 (1.6 versus 2.6; p < 0.001), but ACE concentrations were similar between groups and correlated weakly with ACE-S (r = 0.232). ACE2 and ACE-S trajectories in severe COVID-19, however, did not differ between survivors and non-survivors. Overall RAS alteration in severe COVID-19 resembled severity of disease-matched patients with influenza. In mixed linear models, renin activity most strongly predicted angiotensin II and 1-7 levels. ACE2 also predicted angiotensin 1-7 levels and ALT-S. No single factor or the combined model, however, could fully explain ACE-S. ACE2 and ACE-S trajectories in severe COVID-19 did not differ between survivors and non-survivors. In conclusion, angiotensin II was elevated in severe COVID-19 but was markedly influenced by RAS inhibitors and driven by overall RAS activation. ACE-S was significantly lower with severe COVID-19 and did not correlate with ACE concentrations. A shift to the alt-RAS axis because of increased ACE2 could partially explain the relative reduction in angiotensin II levels.

Factors associated with the progression of mesangial lesions in IgA nephropathy: A comparative analysis of renal re-biopsies.

IgA nephropathy (IgAN) is the most common primary glomerular disease, and is the leading cause of chronic renal failure. Because mesangial lesions are the main pathological changes seen in IgAN, we investigated factors associated with the progression of mesangial lesions in IgAN. We enrolled participants with IgAN who underwent repeat renal biopsies. Based on the progression of mesangial proliferative lesions, the participants were divided into progressive and stable groups. The progression group included participants with a ratio of mesangial cell proliferation score ≥ 1.1 (i.e., proliferation of > 10%) in the second biopsy specimen compared to the first biopsy specimen. The stable group included participants who did not fulfill the aforementioned criteria. We recorded the laboratory parameters, expression of renin-angiotensin system (RAS) receptors (angiotensin II type 1 receptor [AT1R], angiotensin II type 2 receptor [AT2R], Mas receptor [MasR], and the Mas-related G protein-coupled receptor, member D [MrgD]) and mesangial matrix proteins (collagen [Col] IV, fibronectin [FN] and laminin) at the first and second renal biopsies, and the use of immunosuppressive therapy and/or RAS blockers after the first biopsy. We enrolled 24 patients with IgAN who underwent repeat renal biopsies. Half of patients showed progression of mesangial lesions on repeat renal biopsy after a median of 4.3 (1-6) years. The progression group had significantly higher expression levels of AT1R and mesangial matrix proteins (Col IV and FN), and significantly lower expression of AT2R and MasR, compared to the stable group. Multivariate analysis showed that the use of RAS blockers (hazard ratio [HR], 0.27; 95% CI, 0.08-0.97; p < 0.05) and the level of proteinuria (HR, 1.8; 95% CI, 1.04-3.12; p < 0.05) were associated with progression of mesangial lesions. Additionally, the progression group exhibited a more rapid decline of renal function compared to the stable group (0.38 and 0.012 ml/min/1.73 m2/month, respectively; p = 0.004). Continuous activation of the intrarenal RAS and massive proteinuria correlate with histological progression of mesangial lesions in IgAN patients, which may further accelerate the deterioration of renal function.

Current trends in the use of the renin-angiotensin system blocking drugs in renovascular arterial hypertension

Renovascular hypertension (RH) is one of the most common secondary forms of arterial hypertension, in most cases caused by atherosclerotic renal artery stenosis (ARAS). The development of a course of hypertension resistant to antihypertensive therapy with an unfavorable prognosis of deterioration of kidney function and cardiovascular complications is characteristic. The review discusses the pathophysiological mechanisms of RH development in ARAS, draws attention to the important role of the renin-angiotensin system (RAS) activation, which determines the nature of the course of the disease, the high frequency of target organ damage. Modern approaches to the drug treatment of this form of hypertension, the validity and benefits of the use of drugs that block the effects of RAS in patients with RH of atherosclerotic genesis, constituting a category of high risk of cardiovascular complications, are The issues of the effectiveness of the use of these drugs in order to reduce the risk of cardiovascular complications and improve the long-term prognosis of the course of this form of hypertension are discussed.