Arm Of Renin-angiotensin System Research Articles

Gestationally administered RAS modulators reprogram endotoxic cardiovascular and inflammatory profiles in adult male offspring of preeclamptic rats.

Previous studies showed that preeclampsia (PE) amplifies cardiovascular dysfunction induced by endotoxemia in adult male, but not female, offspring. Here, we asked if such aggravated endotoxic insult could be nullified by modulators of the renin-angiotensin system (RAS). PE was induced by gestational administration of Nω-nitro-L-arginine methyl ester(L-NAME, a nitric oxide synthase inhibitor). Adult male offspring of PE mothers treated gestationally with angiotensin 1-7 (Ang1-7, angiotensin II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (peroxisome proliferator-activated receptor gamma, PPARγ, agonist), or combined losartan/pioglitazone were instrumented with femoral indwelling catheters and challenged intravenously with a 5-mg/kg dose of lipopolysaccharides (LPS, 5mg/kg). LPS caused significant decreases in blood pressure (BP) and spectral index of overall heart rate variability and increases in heart rate and left ventricular contractility (dP/dtmax). These effects were mostly reduced to similar magnitudes by individual drug therapies. In offspring born to Ang1-7-treated dams, the spectral index of cardiac sympathovagal balance showed elevated sympathetic dominance in response to LPS. Immunohistochemistry revealed that Ang1-7, but not losartan/pioglitazone, abolished the exaggerated increases in toll-like receptor 4 (TLR-4) expression caused by PE/LPS in heart tissues and neuronal circuits of brainstem rostral ventrolateral medulla (RVLM). By contrast, the losartan/pioglitazone regimen, but not Ang1-7, decreased and increased angiotensin converting enzyme (ACE) and ACE2 expression, respectively. Together, gestational fetal reprogramming of Ang II (depression) and Ang1-7 (activation) arms of RAS effectively counterbalance worsened endotoxic cardiovascular and inflammatory profiles in adult male offspring of PE rats.

The Renin-Angiotensin System Involvement in Cisplatin-Induced Nephrotoxicity: An Overview of Physiological and Pathological Mechanisms-A Systematic Review.

Cisplatin (CDDP) is a highly potent chemotherapy drug. But its nephrotoxicity poses a significant limitation to its use. The renin-angiotensin system (RAS) has been proposed to play a role in drug-induced nephrotoxicity. This systematic review (SR) sought to identify the link between CDDP-induced nephrotoxicity and the RAS pathway. In this SR, relevant keywords were employed to explore databases such as PubMed (MEDLINE), Scopus (Elsevier), and Institute for Scientific Information (ISI) Web of Science up to October 2023. Nine studies were selected based on predefined inclusion/exclusion criteria. The findings support the involvement of the RAS in the CDDP-induced nephrotoxicity model, along with the activation of inflammatory mediators, lipid peroxidation, and changes in markers of kidney tissue damage. Furthermore, physiology and pathology of RAS-related interventions in CDDP-induced nephrotoxicity models have involved the factors such as human organic cation transporter 2 (hOCT2), organic anion transporting polypeptides 1B1 (OATP1B1) and 1B3, kallikrein-kinin system, and bradykinin receptors. CDDP-induced nephrotoxicity has been found to be substantially influenced by both classic and nonclassic RAS axes. Angiotensin II exacerbates renal damage induced by CDDP. Conversely, inhibiting the pressor arm of RAS in males mitigates this damage. However, activation of the renal vasodepressor arm of RAS exacerbates CDDP-induced nephrotoxicity in females. These findings underscore gender differences in renal function and response to RAS-related interventions in the presence of CDDP. This SR provides insights into both beneficial and adverse interventions associated with RAS in the CDDP-induced nephrotoxicity, offering valuable considerations for researchers and clinicians.

Preclinical Evidence for the Role of the Yin/Yang Angiotensin System Components in Autism Spectrum Disorder: A Therapeutic Target of Astaxanthin.

Autism spectrum disorder (ASD) prevalence is emerging with an unclear etiology, hindering effective therapeutic interventions. Recent studies suggest potential renin-angiotensin system (RAS) alterations in different neurological pathologies. However, its implications in ASD are unexplored. This research fulfills the critical gap by investigating dual arms of RAS and their interplay with Notch signaling in ASD, using a valproic acid (VPA) model and assessing astaxanthin's (AST) modulatory impacts. Experimentally, male pups from pregnant rats receiving either saline or VPA on gestation day 12.5 were divided into control and VPA groups, with subsequent AST treatment in a subset (postnatal days 34-58). Behavioral analyses, histopathological investigations, and electron microscopy provided insights into the neurobehavioral and structural changes induced by AST. Molecular investigations of male pups' cortices revealed that AST outweighs the protective RAS elements with the inhibition of the detrimental arm. This established the neuroprotective and anti-inflammatory axes of RAS (ACE2/Ang1-7/MasR) in the ASD context. The results showed that AST's normalization of RAS components and Notch signaling underscore a novel therapeutic avenue in ASD, impacting neuronal integrity and behavioral outcomes. These findings affirm the integral role of RAS in ASD and highlight AST's potential as a promising treatment intervention, inviting further neurological research implications.

Effects of Angiotensin 1-7 Binding on the Dynamics of Human MAS Proto-Oncogene, GPCR: A Molecular Dynamics Study

The understanding of the connections between Angiotensin peptides with the receptors in the Renin-angiotensin system (RAS) is not clear yet. The ACE2/Ang (1-7)/MAS axis, commonly referred to as the protective arm of the RAS, plays a crucial role in maintaining homeostasis within the cardiovascular system. Angiotensin 1-7 (Ang 1-7) is a heptapeptide an integral part of the protective arm of RAS and acts as a ligand binding to the MAS receptor. Understanding the signaling system of the ACE2/Ang (1-7)/MAS axis, which occupies an important place in the RAS, can be considered a serious putative target for the development of new cardiovascular and cancer drugs. It is very important to understand whether the Ang (1-7) ligand binds stably to MAS and, if so, how this affects the dynamics of the receptor. Therefore, we investigated how Ang (1-7) binding affects the stability and communication of the MAS receptor by utilizing molecular dynamics (MD) simulations and various computational techniques. Results indicated that Ang (1-7) was stably bonded to the MAS receptor over the 300[Formula: see text]ns simulation period. It was also observed that ligand binding caused a reduction in the fluctuations of the MAS residues. Major changes include a reduction in flexibility of the N-terminal domain, ICL1, ECL1, ECL2, ECL3, TM6 and C-terminal domain residues. Our findings presented in this study may provide a contribution to future studies seeking to gain a deeper understanding of the role of Ang (1-7) interaction with the MAS receptor in the RAS.

RAS Imbalances Account for Baroreflex Dysfunction and Neuroinflammation Induced by Postpartum Endotoxemia in Weaning Preeclamptic Rats

We recently reported that postpartum endotoxemia induced by lipopolysaccharides (LPS) provokes greater attenuation of arterial baroreflexes in weaning preeclamptic (PE) rats. Considering the role of renin‐angiotensin system (RAS) in PE programming, we investigated whether pharmacologic RAS modulation alters PE programming of baroreceptor dysfunction induced by endotoxemia. PE was induced by depriving pregnant rats of nitric oxide via gestational L‐NAME administration. RAS modulation involved gestational treatment with Ang 1‐7, losartan, pioglitazone, or combined losartan/pioglitazone. Arterial baroreflexes were assessed with the vasoactive method, which measures negative and positive chronotropism following blood pressure manipulations evoked by phenylephrine (PHE) or sodium nitroprusside (SNP). Slopes of the baroreflex curves were recruited as indicators of baroreflex sensitivity (BRSPHE and BRSSNP). All therapeutic regimens, but Ang 1‐7, abolished the rises in blood pressure seen in weaning PE dams. In contrast to no effect for losartan or pioglitazone, the shifts in baroreflex curves and reductions in BRSSNP in weaning PE/LPS mothers were reversed in dams treated gestationally with Ang 1‐7 or losartan/pioglitazone therapy. Alternatively, the concomitantly impaired BRSPHE was solely improved by the combined losartan/pioglitazone therapy. Immunohistochemical studies revealed upregulated TLR‐4/ACE expression and downregulated ACE2 expression in brainstem neuronal pools of PE/LPS rats. These effects were distinctly affected by gestational therapies as Ang 1‐7 reversed the altered brainstem expression of TLR‐4/ACE2, while gestational losartan/pioglitazone reversed the augmented ACE expression. Together, gestational targeting of offensive (ACE/Ang II (suppression) and defensive (ACE2/Ang 1‐7, facilitation) arms of RAS offers a reprogramming strategy against brainstem neuroinflammation and consequent baroreceptor depression caused by endotoxemia in weaning PE dams.

The Identikit of Patient at Risk for Severe COVID-19 and Death: The Dysregulation of Renin-Angiotensin System as the Common Theme.

Since the first months of the coronavirus disease 2019 (COVID-19) pandemic, several specific physiologic traits, such as male sex and older age, or health conditions, such as overweight/obesity, arterial hypertension, metabolic syndrome, and type 2 diabetes mellitus, have been found to be highly prevalent and associated with increased risk of adverse outcomes in hospitalized patients. All these cardiovascular morbidities are widespread in the population and often coexist, thus identifying a common patient phenotype, characterized by a hyper-activation of the “classic” renin-angiotensin system (RAS) and mediated by the binding of angiotensin II (Ang II) to the type 1-receptor. At the same time, the RAS imbalance was proved to be crucial in the genesis of lung injury after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, where angiotensin-converting-enzyme-2 (ACE2) is not only the receptor for SARS-CoV-2, but its down-regulation through internalization and shedding, caused by the virus binding, leads to a further dysregulation of RAS by reducing angiotensin 1-7 (Ang 1-7) production. This focused narrative review will discuss the main available evidence on the role played by cardiovascular and metabolic conditions in severe COVID-19, providing a possible pathophysiological link based on the disequilibrium between the two opposite arms of RAS.

Mechanisms of neuro- and cardioprotection of MAS agonists in the TAC model.

Alzheimer's (AD) is a debilitating disease characterized by a loss of memory and executive function. A growing number of studies have shown a direct correlation between hypertension and increased risk of AD-like symptoms, including cognitive deficits, increased Aβ production and neuronal death. Furthermore, Renin-Angiotensin System (RAS) targeted anti-hypertensives reduce risk. This has prompted studies demonstrating that the protective arm of RAS, via activation of the MAS receptor, is reduced in AD patients, suggesting MAS agonists may protect against ROS production and exotoxicity while also increasing cognition and being cardioprotective. We hypothesize that MAS agonists can ameliorate AD-like pathology in mice using a model of heart failure - transverse aortic constriction (TAC). One week after TAC surgery, C57Bl/6J male mice (8-10wk) started treatment with saline or one of four Mas agonists. Four weeks after surgery, cardiac function was assessed by echocardiography followed by cognitive assessment (10 weeks) using novel object recognition. At 90days, brain, heart and blood were collected and analyzed for phenotypic and functional changes. TAC surgery induced marked morphological changes in cardiac tissue (cardiomyocyte area, fibrosis and apoptosis). The subsequent dysfunction manifested as decreases in standard cardiac measures of left ventricular function and by extension - cognition, which were rescued by MAS agonists. This treatment effect is partly due to a protection of the mitochondrial oxidative phosphorylation pathway rather than biogenesis. Specifically, marked ROS-induced mitochondrial dysfunction occurring within neurons and microglia were reduced with MAS agonist treatment. Further Seahorse analysis revealed a resistance to TAC-induced reductions in mitochondrial complex activity. This trend extended to the heart, improving outcomes for endothelial cells and cardiomyocytes. The Mas agonist RASRx1902 significantly decreased several measures of AD-like pathology in the TAC model with particular focus on cardioprotection and mitochondrial function, indicating that it may be beneficial in those with hypertension as a risk factor for AD development. Future work will focus on further characterizing RASRx1902 effects in affected cellular pathway changes, efficacy in a pilot study examining cerebral blood flow, blood brain barrier integrity, and effects on neuronal function.

Maternal and Fetal Defects of Gestational Angiotensin 1‐7 Receptor Antagonism: A Possible Preclinical Model of Preeclampsia

Preeclampsia (PE) is a complex pathological state associated with serious adverse maternal and fetal consequences. Imbalances of the pressor ACE/Ang II and depressor ACE2/Ang 1-7 arms of renin-angiotensin system are implicated in PE pathophysiology. The current experimental study investigated whether the blockade of Ang 1-7 receptors (Mas receptors) during late pregnancy would replicate clinical features of PE. Two different dosing regimens of A779 (Mas receptor antagonist, 0.750 and 1.3 mg/kg/day s.c.) were administered daily to pregnant rats for 7 consecutive days starting from gestational day 14. The developed maternal and fetal abnormalities were compared to those produced by gestational L-NAME administration (50 mg/kg/day for 7 days), a standard model of PE in rodents. Gestational administration of L-NAME or A779 reduced weight and number of placentas and pups and increased death and resorption percentages of pups. These effects were more evident with the lower dose of A779 than with the higher dose. Moreover, A779 or L-NAME provoked similar elevations in systolic blood pressure and proteinuria. Immunohistochemical studies on placental tissues revealed enhanced protein expression of NFκB in dams treated with L-NAME or the lower, but not higher, dose of A779. While placental ACE expression remained unaltered, ACE2 expression was upregulated by A779 and L-NAME. Studies in isolated perfused kidneys demonstrated diminished acetylcholine vasodilation in L-NAME, but not A779, challenged preparations. Neither drug affected renal vasoconstriction induced by Ang II or phenylephrine. The current data highlight the likelihood of exploiting pregnant dams with pharmacologically eliminated Mas receptors for PE modeling in rodents. However, more studies are needed to further validate the model fidelity and its intimate resemblance to human PE.

Stimulating the Activity of NEP and ACE2: A Unique Approach to Prevent Dementia

Introduction An overactive renin-angiotensin system (RAS) contributes to the pathogenesis of dementia. Angiotensin-converting enzyme 2 (ACE2) and neprilysin (NEP) converts angiotensin II to angiotensin 1–7, while NEP also breaks down amyloid-beta (Aβ) peptide. We hypothesise that activating the neuroprotective arm of RAS can attenuate neuroinflammation and subsequent dementia. The objective of the study was to determine the ability of a new peptide drug lead ‘2A’ (provisional patent number 2020904375, Australia) to stimulate ACE2 and NEP. Methods High-throughput plate reader based assays: The effect of 2A (9 – 26 µM) and alanine scan analogues of 2A (9 µM) on rhNEP and rhACE2 activity was determined using a quenched fluorescent substrate-based assay. Specific enzyme activity was calculated using a standard curve of 7-methoxy-coumarin-4-acetic acid. Further validation of stimulatory effects of 2A using natural substrates Aβ1–40, Aβ1–42 and angiotensin II: Liquid chromatography-mass spectrometry (LCMS) was used to determine the effect of 2A (9 µM) on the breakdown of Aβ1–40, Aβ1–42 and angiotensin II by NEP. Tissue biodistribution of 2A in C57BL/6J mice: 2A (1 mg/kg) was administered via the intranasal route to 12-week old male C57BL/6J mice. LCMS-MS was used to determine the levels of 2A in several tissues including the brain. Results 2A increased the activity of NEP and ACE2 in a concentration-dependent manner. The Vmax of NEP (0.035 ± 0.002 µmols of substrate cleaved/min) in the presence of 2A was significantly higher compared with enzyme alone (0.008 ± 0.001 µmols of substrate cleaved/min; P<0.001; N=10). Alanine scan of 2A revealed that the present primary structure of 2A was important for stimulating ACE2 and NEP activity. 2A significantly increased NEP-mediated formation of Aβ1–40 (P<0.03), Aβ1–42 (P<0.03) and angiotensin II (P≤0.008) breakdown products compared with respective control. Aβ1–40 levels (8 ± 0.7 as % of initial) was less with NEP + 2A compared to with NEP + scrambled control (42 ± 11%; P=0.02; N=3-4). Levels of 2A detected in brain tissue of C57BL/6J mice was significantly higher compared to 2A levels detected in heart, spleen, kidney and spinal cord tissue when administered through the intranasal route (P<0.03; N=5). Conclusions Our results indicate that 2A stimulates ACE2 and NEP activity, as reflected by the enhanced breakdown of angiotensin II and Aβ. Our findings also indicate that intranasal administration delivers significantly higher levels of 2A to the brain compared to systemic organs, thus suggesting that this route of delivery is highly suitable for pre-clinical studies.

Gestationally Administered RAS Modulators Reprogram Endotoxic Cardiovascular and Inflammatory Profiles in Adult Offspring of Preeclamptic Rats

Preeclampsia (PE) adversely programs fetal cardiovascular integrity and amplifies cardiovascular dysfunction induced by endotoxemia in adult offspring of preeclamptic mothers. Here, we asked if such aggravated endotoxic insult could be nullified by modulators of the renin-angiotensin system (RAS). PE was induced by gestational administration of L-NAME, a nitric oxide synthase inhibitor. Adult male offspring of PE mothers treated gestationally with Ang 1-7 (Ang II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, were instrumented with femoral indwelling catheters and challenged intravenously with a 5 mg/kg dose of lipopolysaccharides (LPS, 5 mg/kg). LPS caused significant increases in heart rate and decreases in blood pressure and spectral index of overall heart rate variability. These effects were similarly reduced by all drug therapies. In offspring born to Ang 1-7-treated dams, the spectral index of cardiac sympathovagal balance showed elevated sympathetic dominance in response to LPS. Further, pioglitazone and its combination with losartan were more effective than Ang 1-7 or losartan in depressing the LPS-evoked increases in left ventricular contractility (dP/dtmax). Immunohistochemical studies revealed that Ang1-7, but not losartan/pioglitazone, regimen abolished the exaggerated increases in TLR-4 expression caused by PE/LPS in heart tissues and neuronal circuits of brainstem rostral ventrolateral medulla. By contrast, ACE expression in the same two areas was reduced by losartan/pioglitazone but not Ang 1-7. Together, gestational fetal reprogramming of Ang II (depression) and Ang 1-7 (activation) arms of RAS effectively counterbalance worsened endotoxic cardiovascular and inflammatory profiles in adult offspring of PE rats.

The Duplicitous Nature of ACE2 in COVID-19 Disease.

The Duplicitous Nature of ACE2 in COVID-19 Disease.

Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

Membrane-bound angiotensin converting enzyme (ACE) 2 serves as a receptor for the Sars-CoV-2 spike protein, permitting viral attachment to target host cells. The COVID-19 pandemic brought into light ACE2, its principal product angiotensin (Ang) 1-7, and the G protein-coupled receptor for the heptapeptide (MasR), which together form a still under-recognized arm of the renin–angiotensin system (RAS). This axis counteracts vasoconstriction, inflammation and fibrosis, generated by the more familiar deleterious arm of RAS, including ACE, Ang II and the ang II type 1 receptor (AT1R). The COVID-19 disease is characterized by the depletion of ACE2 and Ang-(1-7), conceivably playing a central role in the devastating cytokine storm that characterizes this disorder. ACE2 repletion and the administration of Ang-(1-7) constitute the therapeutic options currently tested in the management of severe COVID-19 disease cases. Based on their beneficial effects, both ACE2 and Ang-(1-7) have also been suggested to slow the progression of experimental diabetic and hypertensive chronic kidney disease (CKD). Herein, we report a further step undertaken recently, utilizing this type of intervention in the management of evolving acute kidney injury (AKI), with the expectation of renal vasodilation and the attenuation of oxidative stress, inflammation, renal parenchymal damage and subsequent fibrosis. Most outcomes indicate that triggering the ACE2/Ang-(1-7)/MasR axis may be renoprotective in the setup of AKI. Yet, there is contradicting evidence that under certain conditions it may accelerate renal damage in CKD and AKI. The nature of these conflicting outcomes requires further elucidation.

Ameliorative effect of AT2R and ACE2 activation on ischemic renal injury associated cardiac and hepatic dysfunction

This study explored the role of the depressor arm of renin-angiotensin system (RAS) on ischemic renal injury (IRI)-associated cardio-hepatic sequalae under non-diabetic (ND) and diabetes mellitus (DM) conditions. Firstly, rats were injected with Streptozotocin (55 mg/kg i.p.) to develop DM. ND and DM rats underwent Bilateral IRI followed by 24 h of reperfusion. Further, ND and DM rats were subjected to AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator- Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or its combination therapy. As results, IRI caused cardio-hepatic injuries via altered oxidant/anti-oxidant levels, elevated inflammatory events, and altered protein expressions of ACE, ACE2, Ang II, Ang-(1–7) and urinary AGT. However, concomitant therapy of AT2R agonist and ACE2 activator exerts a protective effect in IRI-associated cardio-hepatic dysfunction as evidenced by inhibited oxidative stress, downregulated inflammation, and enhanced cardio-hepatic depressor arm of RAS under ND and DM conditions.

Abstract 371: Cardiac Fibrosis is Associated With Increased Gut Barrier Leakage and Circulating Peptidoglycan in Type 2 Diabetic Mice With Ace2 Deficiency

Purpose: Cardiac fibrosis is linked with hyperglycemia and increases the risk of cardiovascular complications and heart failure. Despite several advancements, the molecular mechanisms responsible for cardiac fibrosis in diabetes remain unclear. The renin-angiotensin system (RAS) is activated and plays an essential role in diabetes-induced cardiac dysfunctions through activation of Ang II. However, angiotensin converting enzyme 2 (ACE2), the protective arm of RAS, opposes the classical RAS functions mediated by ACE. Previously, we have reported that ACE2 deficient exacerbates hyperglycemia-induced gut dysbiosis, increased gut barrier permeability, and facilities translocation of gut microbial peptides (GMPs) into system circulation in type 1 diabetic mice. Here, we sought to determine whether dysbiosis induced by type 2 diabetes and ACE2 deficiency contributes to cardiac fibrosis. Methods: Toll-like receptor- (TLR-2) associated inflammatory signaling and cardiac fibrosis were studied in WT, db/db, and ACE2 -/y -db/db mice with 4-months of diabetes. The levels of peptidoglycan (PGN), a TLR-2 ligand, were measured by ELISA assay. The markers of gut barriers and inflammatory cytokines were assessed by immunohistochemistry and qRT-PCR. To measure cardiac fibrosis, Masson’s trichrome staining was used to stain collagen fibers. Results: ACE2 -/y -db/db mice exhibited increased myocardial fibrosis as compared with db/db and WT mice. In the myocardium, TLR-2 expression (4 folds, p&lt;0.005) and pro-inflammatory cytokines IL-1β (p&lt;0.001), IL-6 (p&lt;0.0001), and TNF-α (p&lt;0.01 were significantly up-regulated in ACE2 -/y -db/db mice compared with db/db and WT mice. Increased gut barrier permeability as detected by a reduction in expression of tight junction molecules (ZO-1, p120-catenin, and VE-cadherin) and a 2- fold increase in circulating PGN was observed in ACE2 -/y -db/db mice when compared to db/db. Conclusions: These data suggest that PGN and other circulating gut microbial particles may have a deleterious impact on cardiac health by promoting inflammation-mediated fibrosis. In addition to controlling hyperglycemia, strategies aimed at restoring gut barrier integrity may prevent diabetic cardiovascular complications.

Targeting the Protective Arm of the Renin-Angiotensin System to Reduce Systemic Lupus Erythematosus Related Pathologies in MRL-lpr Mice

Patients with Systemic Lupus Erythematosus (SLE) suffer from a chronic inflammatory autoimmune disease that results from the body's immune system targeting healthy tissues which causes damage to various organ systems. Patients with lupus are still in need of effective therapies to treat this complex, multi-system disease. Because polymorphisms in ACE are associated with the activity of SLE and lupus nephritis and based on well-documented renal-protective effects of Renin Angiotensin System (RAS)-modifying therapies, ACE-I are now widely used in patients with SLE with significant efficacy. Our research explores alternate ways of modifying the RAS as a potential for systemic therapeutic benefit in the MRL-lpr mouse model of SLE. These therapeutics include; angiotensin (1-7) [A(1-7)], Nor-Leu-3 Angiotensin (1-7) (NorLeu), Losartan (ARB), and Lisinopril (ACE-I). Daily systemic treatment with all of these RAS-modifying therapies significantly reduced the onset and intensity in rash formation and swelling of the paw. Further, histology showed a corresponding decrease in hyperkeratosis and acanthosis in skin sections. Important immunological parameters such as decreased circulating anti-dsDNA antibodies, lymph node size, and T cell activation were observed. As expected, the development of glomerular pathologies was also attenuated by RAS-modifying therapy. Improved number and health of mesenchymal stem cells (MSCs), as well as reduction in oxidative stress and inflammation may be contributing to the reduction in SLE pathologies. Several studies have already characterized the protective role of ACE-I and ARBs in mouse models of SLE, here we focus on the protective arm of RAS. A(1-7) in particular demonstrates several protective effects that go beyond those seen with ACE-Is and ARBs; an important finding considering that ACE-Is and ARBs are teratogenic and can cause hypotension in this population. These results offer a foundation for further pharmaceutical development of RAS-modifying therapies, that target the protective arm, as novel SLE therapeutics that do not rely on suppressing the immune system.

The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients.

The article describes the rationale for inhibition of the renin-angiotensin system (RAS) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent positive feedback-loop mechanisms. Based purely on experimental studies in which RAS pathway inhibitors were administered in vivo to humans/rodents, a reasonable hypothesis of using inhibitors that block both ACE and ACE2 zinc metalloproteases and their downstream pathways in COVID-19 patients will be proposed. In particular, metal (zinc) chelators and renin inhibitors may work alone or in combination to inhibit the positive feedback loops (initially triggered by SARS-CoV-2 and subsequently sustained by hypoxia independently on viral trigger) as both arms of renin-angiotensin system are upregulated, leading to critical, advanced and untreatable stages of the disease.

SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes.

Individuals with diabetes suffering from coronavirus disease 2019 (COVID-19) exhibit increased morbidity and mortality compared with individuals without diabetes. In this Perspective, we critically evaluate and argue that this is due to a dysregulated renin-angiotensin system (RAS). Previously, we have shown that loss of angiotensin-I converting enzyme 2 (ACE2) promotes the ACE/angiotensin-II (Ang-II)/angiotensin type 1 receptor (AT1R) axis, a deleterious arm of RAS, unleashing its detrimental effects in diabetes. As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. We put forth the hypothesis that during this process, reduced ACE2 could result in clinical deterioration in COVID-19 patients with diabetes via aggravating Ang-II–dependent pathways and partly driving not only lung but also bone marrow and gastrointestinal pathology. In addition to systemic RAS, the pathophysiological response of the local RAS within the intestinal epithelium involves mechanisms distinct from that of RAS in the lung; however, both lung and gut are impacted by diabetes-induced bone marrow dysfunction. Careful targeting of the systemic and tissue RAS may optimize clinical outcomes in subjects with diabetes infected with SARS-CoV-2.

Impact of the Renin-Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives.

The effects of the renin–angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood–brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1–7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1–7)/Mas axis constitutes a protective arm of RAS on the blood–brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.

P0527HYPERGLYCEMIA-ASSOCIATED ACUTE KIDNEY INJURY INCREASES THE SUSCEPTIBILITY TOWARDS NEUROLOGICAL DYSFUNCTION: ROLE OF ANGIOTENSIN II TYPE 2 RECEPTOR AND ANGIOTENSIN-CONVERTING ENZYME 2

Abstract Background and Aims In clinical settings, diabetics remain on higher risk of ischemic renal injury (IRI) than nondiabetic patients. In addition, IRI predisposes distant organs to dysfunction such as neurological impairments via activation of the pressor arm of renin-angiotensin system (RAS). In contrast, the role of depressor arm of RAS on IRI-associated neurological sequalae remains elusive. Hence, this study explored the role of angiotensin II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in IRI-associated neurological dysfunctions under nondiabetic (ND) and diabetes mellitus (DM) condition. Method Type 1 diabetes was induced by injecting streptozotocin (55 mg/kg i.p.). ND and DM rats with bilateral IRI were treated with AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator-Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or in combination therapy. Behavioural, biochemical, and histopathological analysis were done to assess IRI-induced neurological impairment. Moreover, immunohistochemistry, ELISA and qRT-PCR experiments were conducted for molecular mechanism analysis. Result In ND and DM rats, IRI caused hippocampal complications as evidenced by increased MDA and nitrite levels, augmented inflammatory cytokines (granulocyte colony stimulating factor, glial fibrillary acidic protein), altered protein and mRNA expressions of Ang II, Ang-(1-7), AT1R, AT2R and MasR. In contrast, concomitant therapy of C21 and Dize effectively normalised aforementioned hippocampal alterations. The protective effect of combination therapy was exerted due to augmented protein and mRNA levels of depressor arm components. Conclusion The current study demonstrated the protective role of AT2R agonist and ACE2 activator in IRI-associated neurological dysfunction through preventing oxidative stress, inflammation and upregulating brain depressor arm of RAS under ND and DM conditions.

Telmisartan/17β-estradiol mitigated cognitive deficit in an ovariectomized rat model of Alzheimer's disease: Modulation of ACE1/ACE2 and AT1/AT2 ratio

AimsThe higher incidence rate of Alzheimer's disease (AD) among women has led to explorations on the association between estrogen deficiency and AD. Also, usage of antihypertensive drugs has been suggested to reduce the incidence of AD in elderly hypertensive patients. Thus, this study aimed to investigate the effects of telmisartan and/or 17β-estradiol on a cognitively impaired ovariectomized rat model of AD. Main methods75 female Wistar rats were randomly allocated into five groups. One group was sham operated and the other four groups were subjected to ovariectomy, received D-galactose and either untreated or treated with telmisartan and/or 17β-estradiol for 6 weeks. Key findingsOvariectomized rats showed cognitive impairment in Morris water maze and novel object recognition tests, increasing inflammatory biomarkers (tumor necrosis factor-α, and interleukin-1β), increasing AD biomarkers (amyloid beta1-42, and acetylcholine esterase), and over activation of classical arm of renin angiotensin system (RAS) (ACE1/Ang2/AT1) in hippocampi. Also, hippocampi histopathological examination revealed amyloid beta deposition. Whereas, administration of telmisartan and/or 17β-estradiol improved animals' behavior, alleviated histopathological alterations and reduced the level of inflammatory and AD biomarkers, modulated RAS activity favoring the novel neuroprotective arm (ACE2/Ang(1–7)/MasR). SignificanceOur findings suggest that combined administration of both drugs has synergetic neuroprotective effects; supporting their potential application in AD treatment.