Renin-angiotensin System Signaling Research Articles

Pyridostigmine attenuates hypertension by inhibiting activation of the renin-angiotensin system in the hypothalamic paraventricular nucleus.

Activation of the renin-angiotensin system (RAS) triggers oxidative stress and an inflammatory response in the hypothalamic paraventricular nucleus (PVN), in turn increasing the sympathetic hyperactivity that is a major cause of hypertension. Pyridostigmine has cardioprotective effects by suppressing the RAS of myocardial tissue. However, whether pyridostigmine attenuates hypertension by inhibiting the RAS of the PVN remains unclear. We thus investigated the effect and mechanism of pyridostigmine on two-kidney one-clip (2K1C)-induced hypertension. 2K1C rats received pyridostigmine, or not, for 8weeks. Cardiovascular function, hemodynamic parameters, and autonomic activity were measured. The PVN levels of pro-/anti-inflammatory cytokines, oxidative stress, and RAS signaling molecules were evaluated. Our results showed that hypertension was accompanied by cardiovascular dysfunction and an autonomic imbalance characterized by enhanced sympathetic but diminished vagal activity. The PVN levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), reactive oxygen species (ROS), NOX-2, and malondialdehyde (MDA) increased; those of IL-10 and superoxide dismutase (SOD) decreased. Moreover, the RAS signaling pathway was activated, as evidenced by increased levels of the angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the Ang II type 1 receptor (AT1R) and a decreased AT2R level. Pyridostigmine lowered blood pressure and improved cardiovascular function, associated with restoration of the autonomic balance. Meanwhile, pyridostigmine decreased PVN IL-6, TNF-α, ROS, NOX-2, and MDA levels and increased IL-10 and SOD levels. Additionally, pyridostigmine suppressed PVN ACE, Ang II, and AT1R levels and increased AT2R expression. Pyridostigmine attenuated hypertension by inhibiting PVN oxidative stress and inflammation induced by the RAS.

Renin-Angiotensin System Signaling in Parietal Epithelial Cells

INTRODUCTION. Bowman's capsule surrounds the kidney glomerular tuft and consists of a monolayer of parietal epithelial cells (PECs) creating a physiologically functioning barrier between the urinary space and the renal interstitium. Pathophysiological PEC activation describes the phenotypic switch from their normal quiescent state to one of proliferation and migration to the glomerular tuft, leading to glomerular injury. The development of several proteinuric kidney diseases is closely associated with PEC activation, however, the mechanisms of functional receptor signaling in these cells are not well described. This study investigates the functional presence of renin-angiotensin system (RAS) components and corresponding intracellular mechanisms in PECs. Methods. The vibrodissociation method was utilized to obtain freshly isolated Bowman’s capsules from discarded adult male human transplant tissues and 12-week old Wistar male and female rats. Confocal fluorescent microscopy of freshly isolated Bowman’s capsule PECs was performed using Fluo-8 or DAF-FM fluorescent dyes to detect changes in intracellular Ca2+ concentrations and nitric oxide (NO) response to the variety of RAS peptides. RESULTS. In separate experiments on freshly isolated rodent and human Bowman’s capsule PECs, we demonstrate the changes in redox response to the stimulation of RAS components. In particular, the acute application of Ang II peptide caused a rapid increase in NO production. Interestingly, we did not indicate significant changes in intracellular Ca2+ influx. To find out which receptor is responsible for the NO release we preincubated PECs with AT1R and AT2R blockers (Losartan and PD123319 respectively). Our data indicate that RAS mediates NO production through the AT2R activation. There is no sex difference was observed in these experiments. Further experiments with the variety of nitric oxide synthase (NOS) pharmacology reveal the functional distribution of NOS in rodent PECs. CONCLUSION. Our study provides an overview of the RAS signaling within PECs. For the first time, we present evidence demonstrating a direct connection between Ang II and redox homeostasis in PECs. Further investigation using the developed approach will be essential for understanding the role of Bowman's capsule cells in the glomerulus and the development of potential treatment against the hyperplasia of activated PECs and corresponding chronic kidney pathologies. Funding Sources: R01 DK129227, R01 DK126720, VA CDA-2 1IK2BX005605-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dysregulation of the renin-angiotensin system in vascular dementia.

The renin-angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (n = 42), Alzheimer's disease (n = 50), mixed AD/VaD (n = 50) and age-matched controls (n = 50). All cases were stratified according to small vessel disease (SVD) severity across both regions. ACE-1 and ACE-2 protein and activity was measured by ELISA and fluorogenic peptide assays respectively, and angiotensin peptide (Ang-II, Ang-III and Ang-(1-7)) levels were measured by ELISA. ACE-1 protein level and enzyme activity, and Ang-II and Ang-III, were elevated in the white matter in vascular dementia in relation to SVD severity. ACE-1 and Ang-II protein levels were inversely related to MAG:PLP1 ratio, a biochemical marker of brain tissue oxygenation that when reduced indicates cerebral hypoperfusion, in a subset of cases. ACE-2 level was elevated in frontal white matter in vascular dementia. Ang-(1-7) level was elevated across all dementia groups compared to age-matched controls but was not related to SVD severity. RAS signalling was not altered in the white matter in Alzheimer's disease. In the overlying frontal cortex, ACE-1 protein was reduced and ACE-2 protein increased in vascular dementia, whereas angiotensin peptide levels were unchanged. These data indicate that RAS signalling is dysregulated in the white matter in vascular dementia and may contribute to the pathogenesis of small vessel disease.

Integrated analysis of genes shared between type 2 diabetes mellitus and osteoporosis.

The relationship between type 2 diabetes mellitus (T2DM) and osteoporosis (OP) has been widely recognized in recent years, but the mechanism of interaction remains unknown. The aim of this study was to investigate the genetic features and signaling pathways that are shared between T2DM and OP. We analyzed the GSE76894 and GSE76895 datasets for T2DM and GSE56815 and GSE7429 for OP from the Gene Expression Omnibus (GEO) database to identify shared genes in T2DM and OP, and we constructed coexpression networks based on weighted gene coexpression network analysis (WGCNA). Shared genes were then further analyzed for functional pathway enrichment. We selected the best common biomarkers using the least absolute shrinkage and selection operator (LASSO) algorithm and validated the common biomarkers, followed by RT-PCR, immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA) to validate the expression of these hub genes in T2DM and OP mouse models and patients. We found 8,506 and 2,030 DEGs in T2DM and OP, respectively. Four modules were identified as significant for T2DM and OP using WGCNA. A total of 19 genes overlapped with the strongest positive and negative modules of T2DM and OP. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed these genes may be involved in pantothenate and CoA biosynthesis and the glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate and renin-angiotensin system signaling pathway. The LASSO algorithm calculates the six optimal common biomarkers. RT-PCR results show that LTB, TPBG, and VNN1 were upregulated in T2DM and OP. Immunofluorescence and Western blot show that VNN1 is upregulated in the pancreas and bones of T2DM model mice and osteoporosis model mice. Similarly, the level of VNN1 in the sera of patients with T2DM, OP, and T2DM and OP was higher than that in the healthy group. Based on the WGCNA and LASSO algorithms, we identified genes and pathways that were shared between T2DM and OP. Both pantothenate and CoA biosynthesis and the glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate and renin-angiotensin systems may be associated with the pathogenesis of T2DM and OP. Moreover, VNN1 may be a potential diagnostic marker for patients with T2DM complicated by OP. This study provides a new perspective for the systematic study of possible mechanisms of combined OP and T2DM.

Studying the Roles of the Renin-Angiotensin System in Accelerating the Disease of High-Fat-Diet-Induced Diabetic Nephropathy in a db/db and ACE2 Double-Gene-Knockout Mouse Model.

Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin-angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity can cause the over-accumulation of angiotensin II (Ang II). Angiotensin-converting enzyme inhibitor (ACEI) administration has been proposed as a therapy, but previous studies have also indicated that chymase, the enzyme that hydrolyzes angiotensin I to Ang II in an ACE-independent pathway, may play an important role in the progression of DN. Therefore, this study established a model of severe DN progression in a db/db and ACE2 KO mouse model (db and ACE2 double-gene-knockout mice) to explore the roles of RAS factors in DNA and changes in their activity after short-term (only 4 weeks) feeding of a high-fat diet (HFD) to 8-week-old mice. The results indicate that FD-fed db/db and ACE2 KO mice fed an HFD represent a good model for investigating the role of RAS in DN. An HFD promotes the activation of MAPK, including p-JNK and p-p38, as well as the RAS signaling pathway, leading to renal damage in mice. Blocking Ang II/AT1R could alleviate the progression of DN after administration of ACEI or chymase inhibitor (CI). Both ACE and chymase are highly involved in Ang II generation in HFD-induced DN; therefore, ACEI and CI are potential treatments for DN.

The role of captopril in leukotriene deficient type 1 diabetic mice

T1D can be associated with metabolic disorders and several impaired pathways, including insulin signaling, and development of insulin resistance through the renin-angiotensin system (RAS). The main precursor of RAS is angiotensinogen (Agt) and this system is often linked to autophagy dysregulation. Dysregulated autophagy has been described in T1D and linked to impairments in both glucose metabolism, and leukotrienes (LTs) production. Here, we have investigated the role of RAS and LTs in both muscle and liver from T1D mice, and its effects on insulin and autophagy pathways. We have chemically induced T1D in 129sve and 129sve 5LO−/− mice (lacking LTs) with streptozotocin (STZ). To further inhibit ACE activity, mice were treated with captopril (Cap). In muscle of T1D mice, treatment with Cap increased the expression of RAS (angiotensinogen and angiotensin II receptor), insulin signaling, and autophagy markers, regardless of the genotype. In the liver of T1D mice, the treatment with Cap increased the expression of RAS and insulin signaling markers, mostly when LTs were absent. 5LO−/− T1D mice showed increased insulin sensitivity, and decreased NEFA, after the Cap treatment. Cap treatment impacted both insulin signaling and autophagy pathways at the mRNA levels in muscle and liver, indicating the potential role of ACE inhibition on insulin sensitivity and autophagy in T1D.

Angiotensin‐converting enzyme‐1, ACE‐1, and ACE‐2 are dysregulated in Alzheimer’s disease and related to ACE1 genotype

AbstractBackgroundThe renin‐angiotensin system (RAS) is dysregulated in Alzheimer’s disease (AD): angiotensin‐converting enzyme (ACE‐1) activity, a rate‐limiting enzyme in the disease‐associated classical RAS (cRAS) pathway, is elevated, whereas ACE‐2 activity, a central mediator of the counter‐regulatory protective pathway (rRAS) (that generates Ang‐(1‐7) from Ang‐II) is defective. Previous meta‐analyses, more recently confirmed in GWAS studies, indicate that ACE1 variants, including an insertion (I)/deletion (D) (indel) polymorphism at intron 16, are risk variants in AD. In this study, we have determined if ACE‐1 and ACE‐2 are dysregulated in AD in relation to ACE1 variant (rs4343) (a proxy marker for the more commonly studied indel polymorphism).MethodWe studied brain tissue from the frontal and parietal cortex from 147 dementia cases (AD (n = 94) and vascular dementia n = 20 and mixed AD/VaD (n = 33)) and 104 age‐matched controls from the South West Dementia Brain Bank, University of Bristol. ACE‐1 and ACE‐2 protein levels were measured by ELISA, and enzyme activities were measured using fluorogenic peptide substrate assays. ACE1 (rs4343) polymorphism was genotyped by PCR.ResultACE‐1 protein level was increased (p<0.0001) and ACE‐2 protein level reduced (p = 0.0103) in AD cases compared to controls in the parietal cortex. In contrast, no significant changes in protein level were observed in the frontal cortex. ACE‐1 enzyme activity was elevated (p<0.0001) as was ACE‐2 enzyme activity in both frontal and parietal cortices (p<0.0001 and p = 0.001 respectively) in AD. Individuals with I/I compared with D/D and I/D genotypes in AD had unchanged ACE‐1 level (p = 0.079), lower ACE‐1 enzyme activity (p = 0.029), higher ACE‐2 level (p = 0.011) and unaltered ACE‐2 enzyme activity (p = 0.085) in the frontal cortex.ConclusionThese data confirm our previous findings showing that RAS is dysregulated in AD. Interestingly, we report regional differences in RAS signalling in AD and a reciprocal relationship between ACE‐2 protein level (reduced) and enzyme activity (increased) in AD that warrants further investigation. RAS appears to be most dysregulated in individuals with an I/I genotype in AD.

Abstract 15056: The Activation of Angiotensin II Type1a Receptors in the SFO and PVN is Necessary to Prime Immunity in Salt Sensitive Hypertension

Introduction: Salt sensitive hypertension (HTN) is associated with increased salt intake and elevated activity of the renin-angiotensin system (RAS) in the brain. We have found that DOCA-salt HTN partly depends on a sympathetic-mediated PlGF release in the spleen. Hypothesis: Whether this effect is related to the contribution of RAS signaling in brain nuclei mediating HTN responses is poorly known. We hypothesized that angiotensin type 1a receptors (AT1aR) within the circumventricular organs (CVOs) could mediate DOCA-salt hypertensive responses. Methods: To discriminate between CVOs, we used 3 mouse model with deletion of AT1aR in 3 in brain CVOs. AT1aRfloxed mice were 1) stereotaxically injected with an adenovirus encoding a Cre-recombinase (or GFP as control), directly in the subfornical organ (SFO), or 2) crossed with Sim1Cre+ (and Sim1Cre- as control) mice to delete the gene in the paraventricular nucleus of hypothalamus (PVN) or 3) crossed with Phox2bCre+ (and Phox2bCre- as control) mice to delete the gene in the dorsal motor nucleus of the vagus nerve (DMV). T Results: We implanted mice with pellets of DOCA or placebo, as control, and salt in drinking water for 3 weeks finding that: AT1aRfloxed mice + Virus encoding Cre Recombinase in the SFO and AT1aRfloxed;Sim1Cre+ mice were protected form HTN-DOCA-salt (SFO-SBP mmHg :133±1 vs 106±0,6, ***p>0,0001; PVN-SBP mmHg :144±2 vs 112±2,***p>0,0001 respectively to their controls); whereas AT1aRfloxed;Phox2bCre+ mice had increased blood pressure levels (SBP mmHg :144±1 vs 144±0,7, respectively to control mice). Additionally, deletion of AT1aR in the SFO and PVN attenuated egression of T cells from the spleen and infiltration on target organ with a reduced disruption of renal glomeruli and reduced accumulation of matrix protein in response to DOCA-salt (SFO-Bowman’s size μm 2 1761±150 vs 821±78, respectively, **p<0,001; PVN-Bowman’s size μm 2 3927±212 vs 2805±252, respectively, **p<0,001). Mice KO for AT1aR in the DMV were not protected from organ damage (Bowman’s size μm 2 776 ± 104 vs 1090 ± 94, respectively). Conclusions: ogether, these data indicate that SFO and PVN contribute to blood pressure in the DOCA-salt model of hypertension through AT1aR signaling, while the DMV role was independent from AT1aR.

Altered Gene Expression Within the Renin-Angiotensin System in Normal Aging and Dementia.

The renin-angiotensin system (RAS) is dysregulated in Alzheimer's disease (AD). In this study, we have explored the hypothesis that an -age--related imbalance in brain RAS is a trigger for RAS dysregulation in AD. We characterized RAS gene expression in the frontal cortex from (i) a cohort of normal aging (n = 99, age range = 19-96 years) and (ii) a case-control cohort (n = 209) including AD (n = 66), mixed dementia (VaD + AD; n = 50), pure vascular dementia (VaD; n = 42), and age-matched controls (n = 51). The AD, mixed dementia, and age-matched controls were further stratified by Braak tangle stage (BS): BS0-II (n = 48), BSIII-IV (n = 44), and BSV-VI (n = 85). Gene expression was calculated by quantitative PCR (qPCR) for ACE1, AGTR1, AGTR2, ACE2, LNPEP, and MAS1 using the 2-∆∆Cq method, after adjustment for reference genes (RPL13 and UBE2D2) and cell-specific calibrator genes (NEUN, GFAP, PECAM). ACE1 and AGTR1, markers of classical RAS signaling, and AGTR2 gene expression were elevated in normal aging and gene expression in markers of protective downstream regulatory RAS signaling, including ACE2, MAS1, and LNPEP, were unchanged. In AD and mixed dementia, AGTR1 and AGTR2 gene expression were elevated in BSIII-IV and BSV-VI, respectively. MAS1 gene expression was reduced at BSV-VI and was inversely related to parenchymal Aβ and tau load. LNPEP gene expression was specifically elevated in VaD. These data provide novel insights into RAS signaling in normal aging and dementia.

Sirtuin 6 protects against podocyte injury by blocking the renin-angiotensin system by inhibiting the Wnt1/β-catenin pathway.

Sirtuins (Sirts) are a family of nicotinamide adenine dinucleotide-dependent protein deacetylases that share diverse cellular functions. Increasing evidence shows that Sirts play a critical role in podocyte injury, which is a major determinant of proteinuria-associated renal disease. Membranous nephropathy (MN) is a typical glomerular disease in which podocyte damage mediates proteinuria development. In this study we investigatedthe molecular mechanisms underlying the regulatory roles of Sirt in podocyte injury in MN patients, rats with cationic bovine serum albumin (CBSA)-induced MN and zymosan activation serum (ZAS)-stimulated podocytes. Compared with healthy controls, MN patients showed significant reduction in intrarenal Sirt1 and Sirt6 protein expression. In CBSA-induced MN rats, significant reduction in intrarenal Sirt1, Sirt3 and Sirt6 protein expression was observed. However, only significant decrease in Sirt6 protein expression was found in ZAS-stimulated podocytes. MN patients showed significantly upregulated protein expression of Wnt1 and β-catenin and renin-angiotensin system (RAS) components in glomeruli. CBSA-induced MN rats exhibited significantly upregulated protein expression of intrarenal Wnt1 and β-catenin and their downstream gene products as well as RAS components. Similar results were observed in ZAS-stimulated podocytes. In ZAS-stimulated podocytes, treatment with a specific Sirt6 activator UBCS039 preserved the protein expression of podocin, nephrin and podocalyxin, accompanied by significant inhibition of the protein expression of β-catenin and its downstream gene products, including Snail1 and Twist; treatment with a β-catenin inhibitor ICG-001 significantly preserved the expression of podocyte-specific proteins and inhibited the upregulation of downstream β-catenin gene products accompanied by significant suppression of the protein expression of RAS components. Thus, we demonstrate that Sirt6 ameliorates podocyte injury by blocking RAS signalling via the Wnt1/β-catenin pathway. Sirt6 is a specific therapeutic target for the treatment of podocyte damage-associated renal disease.

INHIBITION OF AT1 RECEPTOR PARTIALLY PREVENTS ENDOVASCULAR ETHANOL INJECTION INDUCED ACUTE PULMONARY HYPERTENSION AND SECONDARY PULMONARY ARTERY REMODELING

Objective: Ethanol can induce acute pulmonary hypertension (APH) during endovascular sclerotherapy and embolization. We aimed to examine whether the inhibition of the AT1 receptor can prevent this pathological phenomenon and assess its related mechanisms. Design and method: A total of 40 male swine (age, approximately six months) were selected and performed with absolute ethanol endovascular injection (jugular vein). Saline was used as the negative control. Preventive administration of losartan was conducted orally for 3 consecutive days before operations. Pulmonary arterial pressure (PAP), femoral arterial pressure (FAP), and heart rate (HR) were monitored during procedures. Venous plasma and fresh pulmonary artery (PA) tissue of 32 swine were harvested immediately after the operation. The remaining eight swine were kept and sacrificed one-month after the operations, and PA tissues were harvested for paraffin embedding procedures. Protein level was detected by Western blotting and ELISA, whereas qRT-PCR was used in mRNA detection. H & E staining and immunohistochemistry (IHC) were conducted to evaluate histopathology. Results: Ethanol injection elevated PAP in all swine. The concentration of renin-angiotensin system (RAS) ligands was elevated in plasma (all P < 0.0001) but not in PA. The level of oxidative stress increased in both plasma and PA. MRNA level of AT1R (P < 0.01, 95% CI: 0.251 to 1.006), not AT2R increased in PA. Losartan failed to inhibit APH after all sessions of ethanol injection, and partially reversed the ethanol-induced PA remodeling (1. H & E staining presented abnormal morphology of PA; 2. CD31 IHC staining indicated the intimal hyperplasia; 3. a-SMA IHC staining suggested the pathomorphology of smooth muscle cells; 4. TNF-a IHC staining showed the infiltration of immune cells). The P38 MAPK was activated after ethanol injection and could be inhibited by losartan (P < 0.01, 95% CI: -0.391 to -0.164). Ethanol also promoted the translocation of the P40-PHOX/P47-PHOX/P67-PHOX complex and the activation of NOX, which was independent from RAS. Conclusions: Endovascular ethanol injection can induce AEPAP mainly by activating RAS and P38 MAPK signaling. Losartan can partially prevent AEPAP and vascular remodeling owing to the promotion of NOX activity by ethanol.

Repurposing of RAS-Pathway Mediated Drugs for Intestinal Inflammation Related Diseases for Treating SARS-CoV-2 Infection

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is an emerging zoonotic virus, which causes Coronavirus Disease 2019 (COVID-19). Entry of coronaviruses into the cell depends on binding of the viral spike (S) proteins to cellular receptors Angiotensin-converting enzyme 2 (ACE2). The virus-mediated reduction of ACE2/Ang1-7 causes flooding of inflammatory cytokines. A similar scenario of hyper immunologic reaction has been witnessed in the context of Intestinal Inflammatory Diseases (IIDs) with the deregulation of ACE2. This review summarizes several IIDs that lead to such susceptible conditions. It discusses suitable mechanisms of how ACE2, being a crucial regulator of the Renin-Angiotensin System (RAS) signaling pathway, can affect the physiology of intestine as well as lungs, the primary site of SARS-CoV-2 infection. ACE2, as a SARS-CoV-2 receptor, establishes a critical link between COVID-19 and IIDs. Intercessional studies targeting the RAS signaling pathway in patients may provide a novel strategy for addressing the COVID-19 crisis. Hence, the modulation of these key RAS pathway members can be beneficial in both instances. However, it's difficult to say how beneficial are the ACE inhibitors (ACEI)/ Angiotensin II type-1 receptor blockers (ARBs) during COVID-19. As a result, much more research is needed to better understand the relationship between the RAS and SARS-CoV-2 infection.

Role of the Renin-Angiotensin System Components in Renal Cell Carcinoma: A Literature Review.

The physiological aspects of renin-angiotensin system (RAS) components are described in this review. Additionally, we present the main results of studies that could indicate an association between alterations in these components and cancer, particularly renal cell carcinoma (RCC). The RAS undergoes a series of homeostatic and modulatory processes that extend to hypertrophy, hyperplasia, fibrosis, and remodeling, as well as angiogenesis, pro-inflammatory responses, cell differentiation, stem cell programming, and hematopoiesis. The link between cancer-related inflammation and RAS signaling converge in the response to tumor hypoxia and oxidative stress mechanisms, particularly with the angiotensin type 1 receptor leading to activation of transcription factors such as nuclear factor κB (NF-κB), as well as members of the signal transducer and activation of transcription (STAT) family and HIF1⍺. Dysregulation of the physiological actions of RAS in the microenvironment of inflammation and angiogenesis promotes tumor cell growth.

The alternative renin-angiotensin-system (RAS) signalling pathway in prostate cancer and its link to the current COVID-19 pandemic.

The renin-angiotensin system is known to maintain blood pressure and body fluids. However, it has been found to consist of at least two major constituents, the classic and the alternative pathway, balancing and supporting each other's signalling in a very intricate way. Current research has shown that the renin-angiotensin system is involved in a broad range of biological processes and diseases, such as cancer and infectious diseases. We conducted a literature review on the interaction of the renin-angiotensin system and prostate cancer and explored the research on the possible impact of the SARS-CoV-2 virus in this context. This review provides an update on contemporary knowledge into the alternative renin-angiotensin system, its role in cancer, specifically prostate cancer, and the implications of the current COVID-19 pandemic on cancer and cancer care. In this work, we aim to demonstrate how shifting the RAS signalling pathway from the classic to the alternative axis seems to be a viable option in supporting treatment of specific cancers and at the same time demonstrating beneficial properties in supportive care. It however seems to be the case that the infection with SARS-CoV-2 and subsequent impairment of the renin-angiotensin-system could exhibit serious deleterious long-term effects even in oncology.

Ursolic acid and SARS-CoV-2 infection: a new horizon and perspective.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) has been identified as the source of a world coronavirus pandemic in 2019. Covid-19 is considered a main respiratory disease-causing viral pneumonia and, in severe cases, leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Although, extrapulmonary manifestations of Covid-19 like neurological, cardiovascular, and gastrointestinal have been confirmed. Exaggerated immune response and release of a high amount of pro-inflammatory cytokines may progress, causing a cytokine storm. Consequently, direct and indirect effects of SARS-CoV-2 infection can evolve into systemic complications due to the progression of hyper inflammation, oxidative stress and dysregulation of the renin-angiotensin system (RAS). Therefore, anti-inflammatory and antioxidant agents could be efficient in alleviating these disorders. Ursolic acid has anti-inflammatory, antioxidant, and antiviral effects; it reduces the release of pro-inflammatory cytokines, improves anti-inflammatory cytokines, and inhibits the production of reactive oxygen species (ROS). In virtue of its anti-inflammatory and antioxidant effects, ursolic acid may minimize SARS-CoV-2 infection-induced complications. Also, by regulating RAS and inflammatory signaling pathways, ursolic acid might effectively reduce the development of ALI in ARDS in Covid-19. In this state, this perspective discusses how ursolic acid can mitigate hyper inflammation and oxidative stress in Covid-19.

Mitigation of Multi-Organ Radiation Injury with ACE2 Agonist Diminazene Aceturate.

The renin-angiotensin system (RAS) is known to regulate the pathogenesis of radiation-induced injury as inhibitors of the RAS enzyme angiotensin converting enzyme (ACE) have established function as mitigators of multi-organ radiation injury. To further elucidate the role of RAS signaling during both the acute and delayed syndromes of radiation exposure, we have evaluated whether pharmacologic modulation of alternate RAS enzyme angiotensin converting enzyme 2 (ACE2) reduces the pathogenesis of multi-organ radiation-induced injuries. Here, we demonstrate pharmacologic ACE2 activation with the small molecule ACE2 agonist diminazene aceturate (DIZE) improves survival in rat models of both hematologic acute radiation syndrome (H-ARS) and multi-organ delayed effects of acute radiation exposure (DEARE). In the H-ARS model, DIZE treatment increased 30-day survival by 30% compared to vehicle control rats after a LD50/30 total-body irradiation (TBI) dose of 7.75 Gy. In the mitigation of DEARE, ACE2 agonism with DIZE increased median survival by 30 days, reduced breathing rate, and reduced blood urea nitrogen (BUN) levels compared to control rats after partial-body irradiation (PBI) of 13.5 Gy. DIZE treatment was observed to have systemic effects which may explain the multi-organ benefits observed including mobilization of hematopoietic progenitors to the circulation and a reduction in plasma TGF-beta levels. These data suggest the ACE2 enzyme plays a critical role in the RAS-mediated pathogenesis of radiation injury and may be a potential therapeutic target for the development of medical countermeasures for acute radiation exposure.

The protective effect of xanthenone against LPS-induced COVID-19 acute respiratory distress syndrome (ARDS) by modulating the ACE2/Ang-1-7 signaling pathway.

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Oryeongsan (Wulingsan) ameliorates impaired ANP secretion of atria from spontaneously hypertensive rats

Oryeongsan (ORS), a herbal medicine formula, has long been used for the treatment of impaired body water balance in Asian countries. Recently, it was shown that ORS administration modulates the renin-angiotensin system (RAS). Purpose of the present study was to determine characteristics of atrial ANP secretion and effects of ORS on the secretion in the atria from spontaneously hypertensive rats (SHR). Normotensive WKY groups (WKY-V, WKY-ORS, WKY-LOS) and hypertensive SHR groups (SHR-V, SHR-ORS, SHR-LOS) treated with vehicle, ORS, and losartan as a positive control group, respectively, were used. Experiments were performed in perfused beating atria (1.3 Hz) allowing atrial distension, acetylcholine (ACh) stimulation, and serial collection of atrial perfusates. The secreted ANP concentration was measured using radioimmunoassay. Interstitial fluid (ISF) translocation was measured using [3H]inulin clearance. Stepwise increase in atrial distension by 1.1, 2.0, and 2.7 cmH2O above basal distension further increased ANP secretion proportionally in the atria from WKY-V, but the response was significantly suppressed in the atria from SHR-V. Cardiomyocyte ANP release, the first step of atrial ANP secretion, was suppressed in the atria from SHR-V compared to those from WKY-V (−8.02 ± 2.86, −15.86 ± 2.27, and −20.09 ± 3.62%; n = 8, for SHR-V vs. 8.59 ± 2.81, 15.65 ± 7.14, and 38.12 ± 8.28%; n = 8, for WKY-V; p < 0.001 for all stepwise distension, respectively). Chronic treatment with ORS reversed the suppressed ANP release in atria from SHR-ORS group (6.76 ± 3.92, 9.12 ± 2.85, and 28.79 ± 1.79% for SHR-ORS; n = 5 vs. SHR-V; n = 8; p = 0.01, p < 0.001, p < 0.001, respectively). The effects of ORS were comparable to those of losartan. Trans-endocardial translocation of ISF, the second step of atrial ANP secretion was similar in the atria from the hypertensive SHR-V and normotensive WKY-V. ACh-induced ANP secretion and cardiomyocyte ANP release were also suppressed in the atria from SHR-V compared to WKY-V and ORS reversed the suppression. These findings were accompanied with accentuation of the AT1 receptor expression and suppression of the AT2/Mas receptor, M2 mACh receptor and GIRK4, a molecular component of KACh channel, expression in the atria from SHR-V. Further, treatment with ORS or losartan reversed the expressions in the groups of SHR-ORS and SHR-LOS. These results show that ANP secretion is suppressed in the atria from SHR in association with accentuation of AT1 receptor and suppression of AT2/Mas receptor and KACh channel expression. Treatment with ORS ameliorates impaired ANP secretion through improving cardiomyocyte ANP release with modulation of the cardiac RAS and muscarinic signaling. These findings provide experimental evidence which supports the effect of ORS on the regulation of atrial ANP secretion in the atria from SHR.

Strategies to minimize heterogeneity and optimize clinical trials in Acute Respiratory Distress Syndrome (ARDS): Insights from mathematical modelling.

SummaryBackgroundMathematical modelling may aid in understanding the complex interactions between injury and immune response in critical illness.MethodsWe utilize a system biology model of COVID-19 to analyze the effect of altering baseline patient characteristics on the outcome of immunomodulatory therapies. We create example parameter sets meant to mimic diverse patient types. For each patient type, we define the optimal treatment, identify biologic programs responsible for clinical responses, and predict biomarkers of those programs.FindingsModel states representing older and hyperinflamed patients respond better to immunomodulation than those representing obese and diabetic patients. The disparate clinical responses are driven by distinct biologic programs. Optimal treatment initiation time is determined by neutrophil recruitment, systemic cytokine expression, systemic microthrombosis and the renin-angiotensin system (RAS) in older patients, and by RAS, systemic microthrombosis and trans IL6 signalling for hyperinflamed patients. For older and hyperinflamed patients, IL6 modulating therapy is predicted to be optimal when initiated very early (<4th day of infection) and broad immunosuppression therapy (corticosteroids) is predicted to be optimally initiated later in the disease (7th – 9th day of infection). We show that markers of biologic programs identified by the model correspond to clinically identified markers of disease severity.InterpretationWe demonstrate that modelling of COVID-19 pathobiology can suggest biomarkers that predict optimal response to a given immunomodulatory treatment. Mathematical modelling thus constitutes a novel adjunct to predictive enrichment and may aid in the reduction of heterogeneity in critical care trials.FundingC.V. received a Marie Skłodowska Curie Actions Individual Fellowship (MSCA-IF-GF-2020-101028945). R.K.J.'s research is supported by R01-CA208205, and U01-CA 224348, R35-CA197743 and grants from the National Foundation for Cancer Research, Jane's Trust Foundation, Advanced Medical Research Foundation and Harvard Ludwig Cancer Center. No funder had a role in production or approval of this manuscript.

The Therapeutic Potential of Targeting the Angiotensin Pathway as a Novel Therapeutic Approach to Ameliorating Post-surgical Adhesions.

Post-surgical adhesion is a common complication after abdominal or pelvic surgeries. Despite improvements in surgical techniques or the application of physical barriers, few improvements have been achieved. It causes bowel obstruction, pelvic pain, and infertility in women and has an adverse effect on the quality of life. Renin-Angiotensin System (RAS) is traditionally considered a blood pressure regulator. However, recent studies have indicated that the RAS plays a vital role in other processes, including oxidative stress, fibrosis, proliferation, inflammation, and wound healing. Angiotensin II (Ang II) is the main upstream effector of the RAS that can bind to the AT1 receptor (ATIR). A growing body of evidence has revealed that targeting Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II type 1 Receptor Blockers (ARBs), and Direct Renin Inhibitors (DRIs) can prevent post-surgical adhesions. Here we provide an overview of the therapeutic effect of RAS antagonists for adhesion. PubMed, EMBASE, and the Cochrane library were reviewed to identify potential agents targeting the RAS system as a potential approach for post-surgical adhesion. Available evidence suggests the involvement of the RAS signaling pathway in inflammation, proliferation, and fibrosis pathways as well as in post-surgical adhesions. Several FDA-approved drugs are used for targeting the RAS system, and some of them are being tested in different models to reduce fibrosis and improve adhesion after surgery, including telmisartan, valsartan, and enalapril. Identification of the pathological causes of post-surgical adhesion and the potential role of targeting the Renin-Angiotensin System may help to prevent this problem. Based on the pathological function of RAS signaling after surgeries, the administration of ARBs may be considered a novel and efficient approach to prevent postsurgical adhesions. Pre-clinical and clinical studies should be carried out to have better information on the clinical significance of this therapy against post-surgical adhesion formation.