Local Renin-angiotensin System Research Articles

The role of renin-angiotensin system in sepsis-associated acute kidney injury: mechanisms and therapeutic implications.

This review aims to explore the relationship between the renin angiotensin system (RAS) and sepsis-associated acute kidney injury (SA-AKI), a common complication in critically ill patients associated with mortality, morbidity, and long-term cardiovascular complications. Additionally, this review aims to identify potential therapeutic approaches to intervene with the RAS and prevent the development of AKI. Recent studies have provided increasing evidence of RAS alteration during sepsis, with systemic and local RAS disturbance, which can contribute to SA-AKI. Angiotensin II was recently approved for catecholamine resistant vasodilatory shock and has been associated with improved outcomes in selected patients. SA-AKI is a common condition that can involve disturbances in the RAS, particularly the canonical angiotensin-converting enzyme (ACE) angiotensin-II (Ang II)/angiotensin II receptor 1 (AT-1R) axis. Increased renin levels, a key enzyme in the RAS, have been shown to be associated with AKI and may also guide vasopressor therapy in shock. In patients with high renin levels, angiotensin II administration may reduce renin concentration, improve intra-renal hemodynamics, and enhance signaling through the angiotensin II receptor 1. Further studies are needed to explore the role of the RAS in SA-AKI and the potential for targeted therapies.

The Pathogenesis of COVID-19-Related Taste Disorder and Treatments.

COVID-19, mainly manifested as acute respiratory distress syndrome, has afflicted millions of people worldwide since 2019. Taste dysfunction is a common early-stage symptom of COVID-19 infection that burdens patients for weeks or even permanently in some cases. Owing to its subjectivity and complexity, the mechanism of taste disorder is poorly studied. Previous studies have reported that the COVID-19 entry receptors are highly expressed in taste buds, thereby intensifying the cytocidal effect. Taste receptor cells are vulnerable to inflammation, and the COVID-19-induced cytokine storm causes secondary damage to taste function. Interferon and various proinflammatory cytokines can trigger cell apoptosis and disrupt the renewal of taste bud stem cells. This immune response can be further enhanced by the accumulation of Angiotensin II (Ang II) caused by an unbalanced local renin-angiotensin system (RAS) system. In addition, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is neurotropic and can invade the brain through the olfactory bulb, affecting the nervous system. Other factors, such as host zinc deficiency, genetic susceptibility, sialic acid, and some neurotransmitters, also contribute to the pathogenesis process. Although several medical interventions have displayed effectiveness, only a few strategies exist for the treatment of postinfectious dysgeusia. Stem cell-based taste regeneration offers promise for long-term taste disorders. Clinical studies have demonstrated that stem cells can treat long COVID-19 through immune regulation. In dysgeusia, the differentiation of taste bud stem cells can be stimulated through exogenous epithelial-derived and neural-derived factors to regenerate taste buds. Tongue organoids are also emerging as functional taste buds, offering new insights into the study of taste regeneration. This review presents the current evidence of the pathogenesis of COVID-19-related dysgeusia, summarizes currently available treatments, and suggests future directions of taste regeneration therapy.

Azilsartan inhibits inflammation-triggered bone resorption and osteoclastogenesis in vivo via suppression of TNF-α expression in macrophages.

Hypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin system (RAS). Angiotensinogen/Angiotensin (ANG) II/Angiotensin II type 1 receptor (AT1R) axis is considered as the core axis regulating RAS activity. Azilsartan is an FDA-approved selective AT1R antagonist that is used to treat hypertension. This study aimed to determine whether azilsartan affects formation of osteoclast, resorption of bone, and the expression of cytokines linked with osteoclastogenesis during lipopolysaccharide (LPS)-triggered inflammation in vivo. In vivo, following a 5-day supracalvarial injection of LPS or tumor necrosis factor-alpha (TNF-α) with or without azilsartan, the proportion of bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, which are identified as osteoclasts on mice calvariae were counted. The mRNA expression levels of TRAP, cathepsin K, receptor activator of NF-κB ligand (RANKL), and TNF-α were also evaluated. In vitro, the effect of azilsartan (0, 0.01, 0.1, 1, and 10 μM) on RANKL and TNF-α-triggered osteoclastogenesis were investigated. Also, whether azilsartan restrains LPS-triggered TNF-α mRNA and protein expression in macrophages and RANKL expression in osteoblasts were assessed. Furthermore, western blotting for analysis of mitogen-activated protein kinases (MAPKs) signaling was conducted. Azilsartan-treated calvariae exhibited significantly lower bone resorption and osteoclastogenesis than those treated with LPS alone. In vivo, LPS with azilsartan administration resulted in lower levels of receptor activator of RANKL and TNF-α mRNA expression than LPS administration alone. Nevertheless, azilsartan did not show inhibitory effect on RANKL- and TNF-α-triggered osteoclastogenesis in vitro. Compared to macrophages treated with LPS, TNF-α mRNA and protein levels were lower in macrophages treated by LPS with azilsartan. In contrast, RANKL mRNA and protein expression levels in osteoblasts were the same in cells co-treated with azilsartan and LPS and those exposed to LPS only. Furthermore, azilsartan suppressed LPS-triggered MAPKs signaling pathway in macrophages. After 5-day supracalvarial injection, there is no difference between TNF-α injection group and TNF-α with azilsartan injection group. These findings imply that azilsartan prevents LPS-triggered TNF-α production in macrophages, which in turn prevents LPS-Triggered osteoclast formation and bone resorption in vivo.

Abstract 100: Activation Of The Skin Renin-angiotensin System Contributes To The Development Of Hypertension

Recent studies suggest skin vasoconstriction and sodium (Na + ) accumulation are associated with hypertension. The skin has a localized renin-angiotensin system (RAS), a key regulator of blood pressure (BP), but its functional role remains unclear. This study aims to investigate the role of skin RAS in hypertension. Skin tissue from 32 individuals, including patients with hypertension, was used to evaluate the association between skin RAS component expression and office BP. Among the RAS components, skin expression of ATRAP (type-1 angiotensin II (Ang II) receptor (AT1R)-associated protein), which selectively inhibits pathological AT1R signaling, was inversely correlated with systolic and diastolic BP (R 2 = 0.12, P < 0.05; R 2 = 0.20, P < 0.05, respectively). To investigate the causal relationship between skin ATRAP and hypertension, mice lacking ATRAP in skin keratinocytes (KO: K14 Cre ;ATRAP flox ) were generated. Telemetry analysis showed that Ang II (500 ng/kg/min)-induced hypertension and related cardiac hypertrophy was exacerbated in KO mice compared to control mice (mean BP, 123.3 ± 4.7 vs. 132.6 ± 3.1 mmHg, n = 5, P < 0.05; heart/body weight, 4.7 ± 0.4 vs. 5.2 ± 0.7, n = 11-12, P < 0.05). KO mice showed increased skin expression of angiotensinogen and AT1R ( P < 0.05 for each; n = 11-12), while those in the kidneys and heart were similar in both groups, suggesting skin-specific enhancement of tissue RAS activity. AT1R blocker treatment eliminated exaggerated Ang II-induced hypertension and enhancement of skin RAS activity in KO mice. Sympathetic nerve activity, plasma volume, and skin Na + content did not differ between the groups. In KO mice, urine volume per water intake increased ( P < 0.001), despite similar body weight changes in both groups, suggesting decreased extra-renal water loss. Consistent with these findings, skin blood flow (22.6 ± 3.8 vs. 16.5 ± 4.5 AU, P < 0.001) and transepidermal water loss (9.0 ± 1.9 vs. 6.5 ± 1.9 g/m 2 /h, P < 0.01) were decreased in KO mice. These differences, including exaggerated Ang II-induced hypertension, were eliminated by skin vasodilation via body temperature elevation. In conclusion, enhanced skin RAS activity contributes to BP elevation via skin vasoconstriction. Skin RAS may be a novel target for treating hypertension.

Association of angiotensin II and receptors in peri-implantation endometrium with microvessel density and pregnancy outcomes of women with recurrent implantation failure after embryo transfer.

Investigate whether local angiotensin II (AngII) and its AngII type 1 and 2 receptors (AT1R, AT2R) in the endometrium are different and correlate with microvessel density in women with reproductive failure and pregnancy outcomes. Endometrium during the window of implantation from 40 women with recurrent miscarriage (RM) and 40 with recurrent implantation failure (RIF) were compared with 27 fertile women. Peri-implantation endometrium from 54 women prior to euploid embryo transfer were collected and compared in women with successful pregnancy and unsuccessful pregnancy. Compared with fertile women, expression of AT2R was significantly lower, while AT1R/AT2R expression ratio was significantly higher in the stroma of the RIF group. Endometrium arteriole MVD was significantly lower and negatively correlated with the AT1R/AT2R expression ratio in the stroma of the RIF group. No significant differences and correlations were found in the RM group. Compared with the pregnancy group, expression of AT1R and AT2R were significantly lower in all compartments, but only AT1R/AT2R ratio was significantly higher in the stroma of the non-pregnancy group. Similarly, endometrium arteriole MVD was also significantly lower and negatively correlated with the AT1R/AT2R ratio in the stroma of the non-pregnancy group. Local renin-angiotensin system is dysregulated in peri-implantation endometrium and associated with abnormal angiogenesis in RIF and poor implantation outcome after embryo transfer.

Genetic Ablation of Prorenin Receptor in the Rostral Ventrolateral Medulla Influences Blood Pressure and Hydromineral Balance in Deoxycorticosterone-Salt Hypertension.

Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRRRVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRRRVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRRRVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the "maintenance" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract.

The AT1/AT2 Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System.

The AT1 receptor has mainly been associated with the pathological effects of the renin-angiotensin system (RAS) (e.g., hypertension, heart and kidney diseases), and constitutes a major therapeutic target. In contrast, the AT2 receptor is presented as the protective arm of this RAS, and its targeting via specific agonists is mainly used to counteract the effects of the AT1 receptor. The discovery of a local RAS has highlighted the importance of the balance between AT1/AT2 receptors at the tissue level. Disruption of this balance is suggested to be detrimental. The fine tuning of this balance is not limited to the regulation of the level of expression of these two receptors. Other mechanisms still largely unexplored, such as S-nitrosation of the AT1 receptor, homo- and heterodimerization, and the use of AT1 receptor-biased agonists, may significantly contribute to and/or interfere with the settings of this AT1/AT2 equilibrium. This review will detail, through several examples (the brain, wound healing, and the cellular cycle), the importance of the functional balance between AT1 and AT2 receptors, and how new molecular pharmacological approaches may act on its regulation to open up new therapeutic perspectives.

Altered local RAS in the liver increased the risk of NAFLD in male mouse offspring produced by in vitro fertilization

BackgroundAssisted reproductive technology (ART) is associated with an increased risk of adverse metabolic health in offspring, and these findings have been demonstrated in animal models without parental infertility issues. However, it is unclear what changes lead to abnormal metabolism. The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. Thus, we focused on the local RAS of the liver, which is the central organ for glucose and lipid metabolism in offspring conceived by in vitro fertilization (IVF), and studied the role of local liver RAS in metabolic diseases.MethodsMale C57BL/6 mouse offspring obtained by natural pregnancy and IVF were fed a standard chow diet or a high-fat diet (HFD) from 4 weeks of age through 16 weeks of age. We assessed glucose and lipid metabolism, hepatic histopathology, and the gene and protein expression of key RAS components. In addition, the blocker losartan was used from 4 weeks of age through 16 weeks of age to investigate the regulatory mechanisms of abnormal local RAS on metabolic activity in the IVF offspring liver.ResultsThe growth trajectories of IVF offspring body and liver weights were different from those of naturally pregnant offspring. Impaired glucose tolerance (IGT) and insulin resistance (IR) occurred in IVF-conceived male offspring. After continuous HFD feeding, male offspring in the IVF group underwent earlier and more severe IR. Furthermore, there was a trend of lipid accumulation in the livers of chow-fed IVF offspring. Hepatic steatosis was also more serious in the IVF offspring after HFD treatment. Type 1 receptor (AT1R), which is the primary receptor mediating the action of angiotensin (Ang) II, has been confirmed to be upregulated in IVF offspring livers. Losartan reduced or even eliminated most of the significant differences between the IVF and NC groups after HFD consumption.ConclusionsThe upregulation of AT1R expression in the liver increased the activity of the local RAS, resulting in abnormal glucose and lipid metabolism and lipid accumulation in the liver, significantly increasing the risk of nonalcoholic fatty liver disease (NAFLD) in IVF offspring.

Gentisic acid protects against diabetic nephropathy in Nicotinamide-Streptozotocin administered male mice by attenuating oxidative stress and inflammation: The role of miR-200a/Keap1/Nrf2 pathway, renin-angiotensin system (RAS) and NF-кB

Oxidative stress and inflammation play a pivotal role in the pathogenesis of diabetic nephropathy (DN). Local renin-angiotensin systems (RAS) contribute to the pathogenesis and progression of DN by exacerbating oxidative stress and inflammation.Gentisic acid (GA), a phenolic compound and also a metabolite of aspirin, is reported to possess antioxidant and anti-inflammatory properties. However, the protective effects of GA against DN remain to be elucidated. Nicotinamide (120 mg/kg) and streptozotocin (65 mg/kg) were used to induce diabetes in male mice. Oral administration of GA once daily for 2 weeks (100 mg/kg) ameliorated diabetes-induced renal injury by reducing plasma creatinine, urea, blood urea nitrogen, and urinary albuminuria levels. Diabetic mice showed a significant increase in total oxidant status and malondialdehyde, along with decreased catalase, superoxide dismutase, and glutathione peroxidase in the kidney tissue, which was ameliorated in the GA-treated mice. Histopathological analysis showed that GA treatment reduced diabetes-induced renal injury. Furthermore, GA treatment was associated with the downregulation of miR-125b, nuclear factor kappa beta (NF-кB), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and upregulation of interleukin-10 (IL-10), miR-200a, and nuclear factor erythroid 2-related factor 2 (Nrf2) in the renal tissue. GA treatment also downregulated angiotensin-converting enzyme 1 (ACE1), angiotensin II receptor 1 (AT1R), and NADPH oxidase 2 (NOX 2) and upregulated angiotensin-converting enzyme 2 (ACE2). In conclusion, the ameliorative effects of GA against DN may be attributed to its powerful antioxidant and anti-inflammatory properties through the downregulation of NF-кB, upregulation of Nrf2, and modulation of RAS in renal tissue.

The mechanism underlying fluoride-induced low-renin hypertension is related to an imbalance in the circulatory and local renin-angiotensin systems

The renin-angiotensin system (RAS) is an important fluid regulation system in the body, and excessive activation of the circulatory or local RAS can increase blood pressure (BP). Excess fluoride can increase BP, although the underlying mechanism related to activation of the RAS remains unclear. Thus, the aim of this study was to elucidate the role of the RAS in fluoride-induced hypertension. Markers of the circulating and local RASs related to pathological changes to the kidneys, myocardium, and aorta were measured. Fluoride reduced serum levels of renin, angiotensin II (Ang II), and angiotensin (1−7) [Ang (1−7)], and dysregulated plasma levels of aldosterone and potassium levels. Excess fluoride can damage the kidneys, myocardium, and aorta, overactivate the renal angiotensin converting enzyme (ACE)-Ang II-angiotensin type 1 receptor axis, and inhibit activation of the ACE2-Ang (1−7)-Mas axis, leading to dysregulation of alpha epithelial sodium channels and significantly increased expression of Ang II in the myocardium and aorta. Hence, excess fluoride can cause low-renin hypertension via an imbalance between the circulatory and local RASs.

Tripeptide IRW Improves AMPK/eNOS Signaling Pathway via Activating ACE2 in the Aorta of High-Fat-Diet-Fed C57BL/6 Mice.

This study aims to investigate the effect of tripeptide IRW on the local renin-angiotensin system (RAS), particularly angiotensin-converting enzyme 2 (ACE2), and their association with signaling pathways in the aorta of a high-fat-diet (HFD)-induced insulin-resistant mouse model. C57BL/6 mice were fed HFD (45% of the total calories) for six weeks, and then IRW was added to the diet (45 mg/kg body weight (BW)) for another eight weeks. ACE2 mRNA expression and protein level(s) were increased (p < 0.05), while angiotensin II receptor (AT1R) and angiotensin-converting enzyme (ACE) protein abundance was significantly reduced (p < 0.05) in the aorta of HFD mice treated by IRW. IRW supplementation also improved glucose transporter 4 (GLUT4) abundance (p < 0.05) alongside AMP-activated protein kinase (AMPK) (p < 0.05), Sirtuin 1 (SIRT1) (p < 0.05), and endothelial nitric oxide synthase (eNOS) (p < 0.05) expression. IRW downregulated the levels of endothelin 1 (ET-1) and p38 mitogen-activated protein kinases (p38 MAPK, p < 0.05). Furthermore, the levels of AMPK and eNOS in vascular smooth muscle cells (VSMCs) were significantly reduced in ACE2 knockdown cells treated with or without IRW (p < 0.01). In conclusion, this study provided new evidence of the regulatory role of IRW on the aortic ACE2 against metabolic syndrome (MetS) in an HFD-induced insulin-resistant model.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

The intrarenal renin-angiotensin system in hypertension: insights from mathematical modelling.

The renin-angiotensin system (RAS) plays a pivotal role in the maintenance of volume homeostasis and blood pressure. In addition to the well-studied systemic RAS, local RAS have been documented in various tissues, including the kidney. Given the role of the intrarenal RAS in the pathogenesis of hypertension, a role established via various pharmacologic and genetic studies, substantial efforts have been made to unravel the processes that govern intrarenal RAS activity. In particular, several mechanisms have been proposed to explain the rise in intrarenal angiotensin II (Ang II) that accompanies Ang II infusion, including increased angiotensin type 1 receptor (AT1R)-mediated uptake of Ang II and enhanced intrarenal Ang II production. However, experimentally isolating their contribution to the intrarenal accumulation of Ang II in Ang II-induced hypertension is challenging, given that they are fundamentally connected. Computational modelling is advantageous because the feedback underlying each mechanism can be removed and the effect on intrarenal Ang II can be studied. In this work, the mechanisms governing the intrarenal accumulation of Ang II during Ang II infusion experiments are delineated and the role of the intrarenal RAS in Ang II-induced hypertension is studied. To accomplish this, a compartmental ODE model of the systemic and intrarenal RAS is developed and Ang II infusion experiments are simulated. Simulations indicate that AT1R-mediated uptake of Ang II is the primary mechanism by which Ang II accumulates in the kidney during Ang II infusion. Enhanced local Ang II production is unnecessary. The results demonstrate the role of the intrarenal RAS in the pathogenesis of Ang II-induced hypertension and consequently, clinical hypertension associated with an overactive RAS.

Azilsartan suppresses the antiapoptotic biomarker and pro-inflammatory cytokines in rat model of cisplatin-induced retinal and optic nerve toxicity.

The local renin-angiotensin system has been discovered in the eyes; thus, this study evaluates the Azilsartan effect in the retina and optic nerve toxicity induced by Cisplatin in vivo. Forty-eight male rats were randomly assigned into six groups of 8 animals. Group 1 was healthy control that received 0.5mL/day of 0.5% carboxymethyl cellulose (CMC) orally (PO). Group 2 received a single dose of the 7.0mg/kg CIS intraperitoneally with 0.5mL/day of 0.5% CMC-PO. Groups 3 and 4 received 3.5 and 7.0mg/kg/day of AZIL-PO, respectively. Groups 5 and 6 received 3.5 and 7.0mg/kg/day of AZIL-PO, respectively together with a single dose of 7.0mg/kg of CIS-IP. The ocular tissue and serum estimated the TNF-α, NF-kβ, and Casp-3. A complete blood count was also measured, and the eye was sent for histological examination. The administration of the 3.5mg/kg AZIL significantly (p < 0.05) reduced the ocular tissue and serum TNF-α, NF-kB, and Casp-3 levels, when given to CIS treated group, while the 7.0mg/kg AZIL does not. Additionally, azilsartan shows no negative impact on the CBC in rats. Finally, the eye histological examination showed a significant (p < 0.05) drop in the signs of inflammation and cellular degeneration, particularly after administration of the 3.5mg/kg AZIL to the CIS-treated group. A low dose of AZIL exerts an anti-inflammation and an anti-apoptotic effect through significant suppression of the pro-inflammatory mediators and an apoptotic biomarker by blocking the local angiotensin II type.

The role of (pro)renin receptor and its soluble form in cardiovascular diseases.

The renin-angiotensin system (RAS) is a major classic therapeutic target for cardiovascular diseases. In addition to the circulating RAS, local tissue RAS has been identified in various tissues and plays roles in tissue inflammation and tissue fibrosis. (Pro)renin receptor (PRR) was identified as a new member of RAS in 2002. Studies have demonstrated the effects of PRR and its soluble form in local tissue RAS. Moreover, as an important part of vacuolar H+-ATPase, it also contributes to normal lysosome function and cell survival. Evidently, PRR participates in the pathogenesis of cardiovascular diseases and may be a potential therapeutic target of cardiovascular diseases. This review focuses on the effects of PRR and its soluble form on the physiological state, hypertension, myocardial ischemia reperfusion injury, heart failure, metabolic cardiomyopathy, and atherosclerosis. We aimed to investigate the possibilities and challenges of PRR and its soluble form as a new therapeutic target in cardiovascular diseases.

Effectiveness of Hydroalcoholic Seed Extract of Securigera securidaca on Pancreatic Local Renin-Angiotensin System and Its Alternative Pathway in Streptozotocin-Induced Diabetic Animal Model.

Available data suggest inhibition of the pancreatic local-renin-angiotensin system (RAS) reduces tissue complications of diabetes. The purpose of the present study was to investigate the effect of hydroalcoholic seed extract of Securigera securidaca (S. securidaca) (HESS) on the pancreatic local-RAS and its alternative pathway. Three doses of HESS were orally administered to three groups of diabetic male Wistar rats, and the results were compared with both diabetic and healthy control groups. After 35 days of treatment, the groups were assessed for the levels of pancreatic local-RAS components, including renin, angiotensinogen, ACE, and Ang II, as well as ACE2 and Ang-(1-7) in the alternative pathway. The effect of herbal medicine treatment on tissue damage status was investigated by evaluating tissue levels of oxidative stress, proinflammatory and anti-inflammatory cytokines, and through histopathological examination of the pancreas. HESS showed a dose-dependent palliative effect on the tissue oxidative stress profile (P < 0.05) as well as the levels of pancreatic local-RAS components (P < 0.05), compared to diabetic control group. Considering the interrelationship between tissue oxidative stress and local-RAS activity, the moderating effect of HESS on this relationship could be attributed to the increase in total tissue antioxidant capacity (TAC) and pancreatic Ang-(1-7) concentration. Decrease in local-RAS activity was associated with decrease in the tissue levels of inflammatory cytokines (IL1, IL6, and TNFα) (P < 0.05) and increase in the levels of anti-inflammatory cytokine of IL-10 (P < 0.05). In addition, histological results were consistent with tissue biochemical results. Due to the reduction of local pancreatic RAS activity as well as oxidative stress and proinflammatory cytokines following treatment with HESS, S. securidaca seed can be proposed as a suitable herbal supplement in the drug-treatment of diabetes.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Physiological and pathological roles of Ang II and Ang- (1-7) in the female reproductive system.

The local Renin-Angiotensin System (RAS) has been demonstrated to exist in a wide range of tissues and organs, In the female reproductive system, it is mainly found in the ovary, uterus and placenta. The RAS system is made up of a series of active substances and enzymes, in addition to the circulating endocrine renin-angiotensin system. The active peptides Angiotensin II (Ang II) and Angiotensin (1-7) (Ang-(1-7)), in particular, appear to have distinct activities in the local RAS system, which also controls blood pressure and electrolytes. Therefore, in addition to these features, angiotensin and its receptors in the reproductive system seemingly get involved in reproductive processes, such as follicle growth and development, as well as physiological functions of the placenta and uterus. In addition, changes in local RAS components may induce reproductive diseases as well as pathological states such as cancer. In most tissues, Ang II and Ang- (1-7) seem to maintain antagonistic effects, but this conclusion is not always true in the reproductive system, where they play similar functions in some physiological and pathological roles. This review investigated how Ang II, Ang- (1-7) and their receptors were expressed, localized, and active in the female reproductive system. This review also summarized their effects on follicle development, uterine and placental physiological functions. The changes of local RAS components in a series of reproductive system diseases including infertility related diseases and cancer and their influence on the occurrence and development of diseases were elucidated. This article reviews the physiological and pathological roles of Ang II and Ang- (1-7) in female reproductive system,a very intricate system of tissue factors that operate as agonists and antagonists was found. Besides, the development of novel therapeutic strategies targeting components of this system may be a research direction in future.

A New Perspective on the Renin-Angiotensin System

Cardiovascular disease (CVD) is the leading cause of death in the world. Hypertension is a serious medical problem not only in adults but also in children and adolescents. The renin-angiotensin-aldosterone system (RAAS) is one of the most important mechanisms regulating blood pressure and the balance of water and electrolytes. According to the latest reports, RAAS acts not only on endocrine but also on paracrine, autocrine, and intracrine. Moreover, RAAS has a component associated with hypotension and cardioprotective effects. These components are called alternative pathways of RAAS. The most important peptide of the alternative pathway is Ang 1-7, which is related to the Mas receptor. Mas receptors have widely known antihypertension properties, including vasodilatation, the release of nitric oxide, and increased production of anti-inflammatory cytokines. Another interesting peptide is angiotensin A, which combines the properties of the classical and alternative pathways. No less important components of RAAS are the proteolytic enzymes angiotensin convertase enzyme type 1 and 2. They are responsible for the functioning of the RAAS system and are a hypertension therapeutic target. Also involved are tissue-specific enzymes that form a local renin-angiotensin system. Currently, a combination of drugs is used in hypertension treatment. These drugs have many undesirable side effects that cannot always be avoided. For this reason, new treatments are being sought, and the greatest hope comes from the ACE2/ang 1-7/MasR axis.

Abstract 11064: Role of Renin-Angiotensin System Axis in Human Abdominal Aortic Aneurysm

Introduction: Renin-Angiotensin System (RAS) regulates the cardiovascular system and has been implicated in the development of abdominal aortic aneurysm (AAA). RAS modulates function via balancing the ACE/Chymase/AngII-AT1 receptor and ACE-2/Ang(1-7)-Mas receptor axis. Preferential activation of the ACE/Chymase/AngII-AT1 receptor pathway of the RAS contributes to dysregulation of cardiovascular system and disease while the Ang(1-7)-MasR axis contributes to anti-inflammatory pathways. Therefore, identifying the RAS axis mechanism involved in growth, progression, or the risk of rupture in AAA humans could bring a novel treatment perspective. Hypothesis: We hypothesize that in the AAA, the local RAS is altered such as it favours the ACE/AngII/AT1R axis while decreasing the ACE-2/Ang(1-7)/MasR pathway, with consequent AAA development. Objective: We sought to investigate the expression of RAS components in the AAA human aorta. Methods: Aorta tissue from AAA patients (n=21) was collected during the AAA conventional repair surgery, and aorta control aortas were obtained from organ donors (Control, n=11). Protein expression of renin, chymase, ACE, ACE-2 AT1, AT2, and MAS receptors was analyzed by Western Blotting. Results: Our AAA cohort consisted mostly males (76.6% AAA vs. 63.6% Control, p=0.68), smokers or ex-smokers (90.4% AAA vs. 36.3% Control, p=0.002) and most of them had hypertension(71.4% AAA vs. 36.3% Control, p=0.07). Analysis of protein expression in the AAA group showed that ACE and AT1 receptors were upregulated compared with Control (p=0.05; p=0.02, respectively,), while chymase expression was decreased in AAA compared to the control (p=0.03). Additionally, the AAA group showed downregulation in ACE-2 and AT2 compared with Control (respectively, p=0.01, p=0.03). There was no significant difference in the expression of renin and MAS receptors between groups (p=0.52, p=0.41, respectively,). Conclusions: Our data show that the ACE/AT1R axis was upregulated while ACE-2 and AT2 receptors were downregulated in the AAA aorta. Our results implicate local RAS in AAA development and warrant further studies.