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A solitary functioning kidney (SFK) from birth predisposes to hypertension and kidney dysfunction, and this may be associated with impaired fluid and sodium homeostasis. Brief and early angiotensin-converting enzyme inhibition (ACEi) in a sheep model of SFK delays onset of kidney dysfunction. We hypothesized that modulation of the renin–angiotensin system via brief postnatal ACEi in SFK would reprogram renal sodium and water handling. Here, blood pressure (BP), kidney haemodynamics and kidney excretory function were examined in response to an isotonic saline load (0.13 ml/kg/min, 180 min) at 20 months of age in SFK (fetal unilateral nephrectomy at 100 days gestation; term 150 days), sham and SFK+ACEi sheep (ACEi in SFK 4–8 weeks of age). Basal BP was higher in SFK than sham (∼13 mmHg), and similar between SFK and SFK+ACEi groups. Saline loading caused a small increase in BP (∼3–4 mmHg) the first 2 h in SFK and sham sheep but not SFK+ACEi sheep. Glomerular filtration rate did not change in response to saline loading. Total sodium excretion was similar between groups. Total urine excretion was similar between SFK and sham animals but was ∼40% less in SFK+ACEi animals compared with SFK animals. In conclusion, the present study indicates that water homeostasis in response to a physiological challenge is attenuated at 20 months of age by brief early life ACEi in SFK. Further studies are required to determine if ACEi in early life in children with SFK could compromise fluid homeostasis later in life. [ABSTRACT FROM AUTHOR]

For years, the AT2R-selective ligand CGP42112 has been erroneously characterized as a partial agonist, partly due to its ability to also interact with the AT1R at high concentrations. As late as 2009, it was still being characterized as an antagonist as well. In this perspective/opinion piece, we try to resolve the ambiguity that surrounds the efficacy of this compound by extensively reviewing the literature, tracing its beginnings to 1989, showing that CGP42112 has never been convincingly shown to be a partial agonist or an antagonist at the AT2R. While CGP42112 is now routinely characterized as an AT2R agonist, regrettably, there is a paucity of studies that can validate its efficacy as a full agonist at the AT2R, leaving the door open for continuing speculation regarding the extent of its efficacy. Hopefully, the information presented in this perspective/opinion piece will firmly establish CGP42112 as a full agonist at the AT2R such that it can once again be used as a tool to study the AT2R. [ABSTRACT FROM AUTHOR]

Systemic arterial hypertension is one of the leading causes of morbidity and mortality in the general population, being a risk factor formany cardiovascular diseases. Although its pathogenesis is complex and still poorly understood, some systems appear to play major roles in its development. This review aims to update the current knowledge on the interaction of the intrarenal renin-angiotensin system (RAS) and dopaminergic system in the development of hypertension, focusing on recent scientific hallmarks in the field. The intrarenal RAS, composed of several peptides and receptors, has a critical role in the regulation of blood pressure (BP) and, consequently, the development of hypertension. The RAS is divided into two main intercommunicating axes: the classical axis, composed of angiotensin-converting enzyme, angiotensin II, and angiotensin type 1 receptor, and the ACE2/angiotensin-(1-7)/Mas axis, which appears to modulate the effects of the classical axis. Dopamine and its receptors are also increasingly showing an important role in the pathogenesis of hypertension, as abnormalities in the intrarenal dopaminergic system impair the regulation of renal sodium transport, regardless of the affected dopamine receptor subtype. There are five dopamine receptors, which are divided into two major subtypes: the D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) receptors. Mice deficient in any of the five dopamine receptor subtypes have increased BP. Intrarenal RAS and the dopaminergic system have complex interactions. The balance between both systems is essential to regulate the BP homeostasis, as alterations in the control of both can lead to hypertension. [ABSTRACT FROM AUTHOR]

It is well-established that Ang-(1-7) counteracts the effects of Ang II in the periphery, while stimulating vasopressin release and mimicking the activity of Ang II in the brain, through interactions with various receptors. The rapid metabolic inactivation of Ang-(1-7) has proven to be a limitation to therapeutic administration of the peptide. To circumvent this problem, Alves et al. (Clinical Science (2021) 135(18), https://doi.org/10.1042/CS20210599) developed a new transgenic rat model that overexpresses an Ang-(1-7)-producing fusion protein. In this commentary, we discuss potential concerns with this model while also highlighting advances that can ensue from this significant technical feat. [ABSTRACT FROM AUTHOR]

Activation of the angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system (RAS) induces protective mechanisms in different diseases. Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein. The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain. Plasma Ang-(1-7) levels, measured by radioimmunoassay (RIA) were similar to control Sprague-Dawley (SD) rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure (MAP), assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma atrial natriuretic peptide (ANP) and higher urinary sodium concentration. Moreover, evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decrease in total peripheral resistance (TPR). TG7371 rats, on the other hand, also presented increased cardiac and global sympathetic tone, increased plasma vasopressin (AVP) levels and decreased free water clearance. Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance. This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower blood pressure (BP). Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions. [ABSTRACT FROM AUTHOR]

Although numerous clinical and experimental studies have clearly identified a sexual dimorphism in blood pressure control, the mechanism(s) underlying gender differences in blood pressure remain unclear. Over the past two decades, numerous laboratories have utilized the spontaneously hypertensive rats (SHR) as an experimental model of essential hypertension to increase our understanding of the mechanisms regulating blood pressure in males and females. Previous work by our group and others have implicated that differential regulation of adrenergic receptors, the renin-angiotensin system, oxidative stress, nitric oxide bioavailability and immune cells contribute to sex differences in blood pressure control in SHR. The purpose of this review is to summarize previous findings to date regarding the mechanisms of blood pressure control in male versus female SHR. [ABSTRACT FROM AUTHOR]

In times of coronavirus disease 2019 (COVID-19), the impact of severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 infection on pregnancy is still unclear. The presence of angiotensin-converting enzyme (ACE) 2 (ACE2), the main receptor for SARS-CoV-2, in human placentas indicates that this organ can be vulnerable for viral infection during pregnancy. However, for this to happen, additional molecular processes are critical to allow viral entry in cells, its replication and disease manifestation, particularly in the placenta and/or feto-maternal circulation. Beyond the risk of vertical transmission, COVID-19 is also proposed to deplete ACE2 protein and its biological actions in the placenta. It is postulated that such effects may impair essential processes during placentation and maternal hemodynamic adaptations in COVID-19 pregnancy, features also observed in several disorders of pregnancy. This review gathers information indicating risks and protective features related to ACE2 changes in COVID-19 pregnancies. First, we describe the mechanisms of SARS-CoV-2 infection having ACE2 as a main entry door and current evidence of viral infection in the placenta. Further, we discuss the central role of ACE2 in physiological systems such as the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS), both active during placentation and hemodynamic adaptations of pregnancy. Significant knowledge gaps are also identified and should be urgently filled to better understand the fate of ACE2 in COVID-19 pregnancies and the potential associated risks. Emerging knowledge will be able to improve the early stratification of high-risk pregnancies with COVID-19 exposure as well as to guide better management and follow-up of these mothers and their children. [ABSTRACT FROM AUTHOR]

Although the existence of a brain renin-angiotensin system (RAS) had been proposed five decades ago, we still struggle to understand how it functions. The main reason for this is the virtual lack of renin at brain tissue sites. Moreover, although renin's substrate, angiotensinogen, appears to be synthesized locally in the brain, brain angiotensin (Ang) II disappeared after selective silencing of hepatic angiotensinogen. This implies that brain Ang generation depends on hepatic angiotensinogen after all. Rodrigues et al. (Clin Sci (Lond) (2021) 135:1353-1367) generated a transgenic mouse model overexpressing full-length rat angiotensinogen in astrocytes, and observed massively elevated brain Ang II levels, increased sympathetic nervous activity and vasopressin, and up-regulated erythropoiesis. Yet, blood pressure and kidney function remained unaltered, and surprisingly no other Ang metabolites occurred in the brain. Circulating renin was suppressed. This commentary critically discusses these findings, concluding that apparently in the brain, overexpressed angiotensinogen can be cleaved by an unidentified non-renin enzyme, yielding Ang II directly, which then binds to Ang receptors, allowing no metabolism by angiotensinases like ACE2 and aminopeptidase A. Future studies should now unravel the identity of this non-renin enzyme, and determine whether it also contributes to Ang II generation at brain tissue sites in wildtype animals. Such studies should also re-evaluate the concept that Ang-(1-7) and Ang III, generated by ACE2 and aminopeptidase A, respectively, have important functions in the brain. [ABSTRACT FROM AUTHOR]

In spite of the fact that the modulatory effects of angiotensin II (Ang II) on the sympathetic nerve activity to targeted organs involved in blood pressure (BP) regulation is well acknowledged, the local production of this peptide in the brain and the consequences of enhanced central Ang II beyond the cardiovascular system are not yet well comprehended. In the present study, we generated and validated a new transgenic mouse line overexpressing the rat full-length angiotensinogen (Agt) protein specifically in the brain (Agt-Tg). Adult Agt-Tg mice presented overall increased gene expression of total Agt in the brain including brainstem and hypothalamus. In addition, the excess of Agt led to abundantly detectable brain Ang II levels as well as increased circulating copeptin levels. Agt-Tg displayed raised BP in acute recordings, while long-term telemetrically measured basal BP was indistinguishable from wild-types. Agt-Tg has altered peripheral renin-angiotensin system and vasomotor sympathetic tone homeostasis because renal gene expression analysis, plasma Ang II measurements and ganglionic blockade experiments revealed suppressed renin expression and reduced Ang II and higher neurogenic pressure response, respectively. Plasma and urine screens revealed apparently normal fluid and electrolyte handling in Agt-Tg. Interestingly, hematological analyses showed increased hematocrit in Agt-Tg caused by enhanced erythropoiesis, which was reverted by submitting the transgenic mice to a long-term peripheral sympathectomy protocol. Collectively, our findings suggest that Agt-Tg is a valuable tool to study not only brain Ang II formation and its modulatory effects on cardiovascular homeostasis but also its role in erythropoiesis control via autonomic modulation. [ABSTRACT FROM AUTHOR]

The data illustrated in their Figure 4 (Panel B) show that brainstem Ang II concentrations were below the level of assay detectability in five of seven rats given the DOCA+salt vehicle treatment compared with all seven rats receiving the siRNA treatment. Potential biological functions of the non-angiotensin coding region of the AGT molecule, named des-(Ang I)-AGT, remains unappreciated [14,22,23]. [Extracted from the article]

Clinical trials indicate that sodium/glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) improve kidney function, yet, the molecular regulation of SGLT2 expression is incompletely understood. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) on SGLT2 expression. In adult non-diabetic participants in the Nephrotic Syndrome Study Network (NEPTUNE, n=163), multivariable linear regression analysis showed SGLT2 mRNA was significantly associated with angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE) mRNA levels (P<0.001). In vitro, angiotensin II (Ang II) dose-dependently stimulated SGLT2 expression in HK-2, human immortalized renal proximal tubular cells (RPTCs); losartan and antioxidants inhibited it. Sglt2 expression was increased in transgenic (Tg) mice specifically overexpressing Agt in their RPTCs, as well as in WT mice with a single subcutaneous injection of Ang II (1.44mg/kg). Moreover, Ang II (1000 ng/kg/min) infusion via osmotic mini-pump in WT mice for 4 weeks increased systolic blood pressure (SBP), glomerulosclerosis, tubulointerstitial fibrosis, and albuminuria; canaglifozin (Cana, 15 mg/kg/day) reversed these changes, with the exception of SBP. Fractional glucose excretion (FeGlu) was higher in Ang II+Cana than WT+Cana, whereas Sglt2 expression was similar. Our data demonstrate a link between intrarenal RAS and SGLT2 expression and that SGLT2i ameliorates Ang II-induced renal injury independent of SBP. [ABSTRACT FROM AUTHOR]

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II)-dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBa degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure. [ABSTRACT FROM AUTHOR]

In the brain, aminopeptidase A (APA), a membrane-bound zinc metalloprotease, generates angiotensin III from angiotensin II. Brain angiotensin III exerts a tonic stimulatory effect on the control of blood pressure (BP) in hypertensive rats and increases vasopressin release. Blocking brain angiotensin III formation by the APA inhibitor prodrug RB150/firibastat normalizes arterial BP in hypertensive deoxycorticosterone acetate (DOCA)-salt rats without inducing angiotensin II accumulation. We therefore hypothesized that another metabolic pathway of brain angiotensin II, such as the conversion of angiotensin II into angiotensin 1-7 (Ang 1-7) by angiotensin-converting enzyme 2 (ACE2) might be activated following brain APA inhibition. We found that the intracerebroventricular (icv) administration of RB150/firibastat in conscious DOCA-salt rats both inhibited brain APA activity and induced an increase in brain ACE2 activity. Then, we showed that the decreases in BP and vasopressin release resulting from brain APA inhibition with RB150/firibastat were reduced if ACE2 was concomitantly inhibited by MLN4760, a potent ACE2 inhibitor, or if the Mas receptor (MasR) was blocked by A779, a MasR antagonist. Our findings suggest that in the brain, the increase in ACE2 activity resulting from APA inhibition by RB150/firibastat treatment, subsequently increasing Ang 1-7 and activating the MasR while blocking angiotensin III formation, contributes to the antihypertensive effect and the decrease in vasopressin release induced by RB150/firibastat. RB150/firibastat treatment constitutes an interesting therapeutic approach to improve BP control in hypertensive patients by inducing in the brain renin-angiotensin system, hyperactivity of the beneficial ACE2/Ang 1-7/MasR axis while decreasing that of the deleterious APA/Ang II/Ang III/ATI receptor axis. [ABSTRACT FROM AUTHOR]

Epilepsy is a highly prevalent neurological disease and anti-epileptic drugs (AED) are almost the unique clinical treatment option. A disbalanced brain renin-angiotensin system (RAS) has been proposed in epilepsy and several reports have shown that angiotensin II (Ang II) receptor-1 (ATR1) activation is pro-inflammatory and pro-epileptogenic. In agreement, ATR1 blockage with the repurposed drug losartan has shown benefits in animal models of epilepsy. Processing of Ang II by ACE2 enzyme renders Ang-(1-7), a metabolite that activates the mitochondrial assembly (Mas) receptor (MasR) pathway. MasR activation presents beneficial effects, facilitating vasodilatation, increasing anti-inflammatory and antioxidative responses. In a recent paper published in Clinical Science, Gomes and colleagues (Clin. Sci. (Lond.) (2020) 134, 2263-2277) performed intracerebroventricular (icv) infusion of Ang-(1-7) in animals subjected to the pilocarpine model of epilepsy, starting after the first spontaneous motor seizure (SMS). They showed that this approach reduced the frequency of SMS, restored animal anxiety, increased exploration, and augmented the hippocampal expression of protective catalase enzyme and antiapoptotic protein B-cell lymphoma 2 (Bcl-2). Interestingly, but surprisingly, Gomes and colleagues showed that MasR expression and mTor activity were reduced in the hippocampus of the epileptic Ang-(1-7) treated animals. These results show that Ang-(1-7) administration could represent a new avenue for developing strategies for the management of epilepsy in clinical settings. However, future work is necessary to evaluate the levels of RAS metabolites and the activity of key enzymes in these experimental interventions to completely understand the therapeutic potential of the brain RAS manipulation in epilepsy. [ABSTRACT FROM AUTHOR]

We comment on the publication of a paper in which Brazilian investigators evaluate the anticontractile response of perivascular adipose tissue (PVAT) in experimental heart failure (HF) induced in rats by occlusion of a coronary artery. [ABSTRACT FROM AUTHOR]

The key link between renin-angiotensin system (RAS) and COVID-19 is ACE2 (angiotensin-converting enzyme 2), which acts as a double-edged sword, because ACE2 increases the tissue anti-inflammatory response but it is also the entry receptor for the virus. There is an important controversy on several drugs that regulate RAS activity and possibly ACE2, and are widely used, particularly by patients most vulnerable to severe COVID-19. In the lung of healthy rats, we observed that candesartan (an angiotensin type-1, AT1, receptor blocker; ARB) and captopril (an ACE inhibitor; ACEI) up-regulated expression of tissue ACE2 and RAS anti-inflammatory axis receptors (AT2 and Mas receptors). This effect was particularly pronounced in rats with metabolic syndrome (obesity, increased blood pressure and hyperglycemia) and aged rats. Treatment of cultures of human type-II pneumocytes with candesartan or captopril induced up-regulation of ACE2 expression in cells. Treatment with viral spike protein induced a decrease in full-length (i.e. transmembrane) ACE2, an increase in levels of a short intracellular ACE2 polypeptide and an increase in ADAM17 activity in cells, together with an increase in levels of soluble ACE2 and major proinflammatory cytokines in the culture medium. Spike protein-induced changes and levels of spike protein internalization in cells were inhibited by pretreatment with the above-mentioned drugs. The results suggest that these drugs increase ACE2 levels and promote the anti-inflammatory RAS axis in the lung. Furthermore, possible up-regulation of viral entry by the drug-induced increase in expression of transmembrane ACE2 is counteracted by additional mechanisms, particularly by drug-induced inhibition of ADAM17 activity. [ABSTRACT FROM AUTHOR]

A high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto-Kakizaki (GK) and Wistar rats treated with two different classes of ß-blocker or vehicle, utilising synchrotron-based microangiography in vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin-angiotensin-aldosterone system (RAAS) overactivation. [ABSTRACT FROM AUTHOR]

Diabetes increases the risk for ischemic vascular diseases, which is further elevated in older adults. Bone marrow-derived hematopoietic CD34+ stem/progenitor cells have the potential of revascularization; however, diabetes attenuates vasoreparative functions. Angiotensin-converting enzyme 2 (ACE2) is the vasoprotective enzyme of renin-angiotensin system in contrast with the canonical angiotensin-converting enzyme (ACE). The present study tested the hypothesis that diabetic dysfunction is associated with ACE2/ACE imbalance in hematopoietic stem/progenitor cells (HSPCs) and that increasing ACE2 expression would restore reparative functions. Blood samples from male and female diabetic (n=71) or nondiabetic (n=62) individuals were obtained and CD34+ cells were enumerated by flow cytometry. ACE and ACE2 enzyme activities were determined in cell lysates. Lentiviral (LV) approach was used to increase the expression of soluble ACE2 protein. Cells from diabetic older adults (DB) or nondiabetic individuals (Control) were evaluated for their ability to stimulate revascularization in a mouse model of hindlimb ischemia (HLI). DB cells attenuated the recovery of blood flow to ischemic areas in nondiabetic mice compared with that observed with Control cells. Administration of DB cells modified with LV-ACE2 resulted in complete restoration of blood flow. HLI in diabetic mice resulted in poor recovery with amputations, which was not reversed by either Control or DB cells. LV-ACE2 modification of Control or DB cells resulted in blood flow recovery in diabetic mice. In vitro treatment with Ang-(1-7) modified paracrine profile in diabetic CD34+ cells. The present study suggests that vasoreparative dysfunction in CD34+ cells from diabetic older adults is associated with ACE2/ACE imbalance and that increased ACE2 expression enhances the revascularization potential. [ABSTRACT FROM AUTHOR]

Brain renin-angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6-8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin IIwas detected in all rats, whereas brainstem angiotensin IIwas detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19+- 1 mmHg and suppressed circulating renin and angiotensin II by>90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (<6 fmol/g). Gene silencing of liver angiotensinogen using siRNA lowered circulating angiotensinogen by 97+-0.3%, and made brainstem angiotensin II undetectable in all rats (P<0.05 vs. non-DOCA-salt), although brainstem angiotensinogen remained intact. As expected for this model, neither siRNA nor valsartan attenuated the hypertensive response to DOCA-salt, whereas spironolactone normalized blood pressure and restored brain angiotensin II together with circulating renin and angiotensin II. In conclusion, despite local synthesis of angiotensinogen in the brain, brain angiotensin II depended on circulating angiotensinogen. That DOCA-salt suppressed circulating and brain angiotensin II in parallel, while spironolactone simultaneously increased brain angiotensin II and lowered blood pressure, indicates that DOCA-salt hypertension is not mediated by brain RAS activation. [ABSTRACT FROM AUTHOR]

Cardiometabolic diseases (CMDs) are among the most prevalent and the highest mortality diseases. Single disease etiology such as gene mutation, polymorphisms, or environmental exposure has failed to explain the origin of CMD. This can be evident in the discrepancies in disease susceptibility among individuals exposed to the same environmental insult or who acquire the same genetic variation. Epigenetics is the intertwining of genetic and environmental factors that results in diversity in the disease course, severity, and prognosis among individuals. Environmental exposures modify the epigenome and thus provide a link for translating environmental impact on changes in gene expression and precipitation to pathological conditions. Renin-angiotensin system (RAS) is comprising genes responsible for the regulation of cardiovascular, metabolic, and glycemic functions. Epigenetic modifications of RAS genes can lead to overactivity of the system, increased sympathetic activity and autonomic dysfunction ultimately contributing to the development of CMD. In this review, we describe the three common epigenetic modulations targeting RAS components and their impact on the susceptibility to cardiometabolic dysfunction. Additionally, we highlight the therapeutic efforts of targeting these epigenetic imprints to the RAS and its effects. [ABSTRACT FROM AUTHOR]

The rapid spread of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought into focus the key role of angiotensin-converting enzyme 2 (ACE2), which serves as a cell surface receptor required for the virus to enter cells. SARS-CoV-2 can decrease cell surface ACE2 directly by internalization of ACE2 bound to the virus and indirectly by increased ADAM17 (a disintegrin and metalloproteinase 17)-mediated shedding of ACE2. ACE2 is widely expressed in the heart, lungs, vasculature, kidney and the gastrointestinal (GI) tract, where it counteracts the deleterious effects of angiotensin II (AngII) by catalyzing the conversion of AngII into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). The down-regulation of ACE2 by SARS-CoV-2 can be detrimental to the cardiovascular system and kidneys. Further, decreased ACE2 can cause gut dysbiosis, inflammation and potentially worsen the systemic inflammatory response and coagulopathy associated with SARS-CoV-2. This review aims to elucidate the crucial role of ACE2 both as a regulator of the renin-angiotensin system and a receptor for SARS-CoV-2 as well as the implications for Coronavirus disease 19 and its associated cardiovascular and renal complications. [ABSTRACT FROM AUTHOR]

Perivascular adipose tissue (PVAT) dysfunction is associated with vascular damage in cardiometabolic diseases. Although heart failure (HF)-induced endothelial dysfunction is associated with renin-angiotensin system (RAS) activation, no data have correlated this syndrome with PVAT dysfunction. Thus, the aim of the present study was to investigate whether the hyperactivation of the RAS in PVAT participates in the vascular dysfunction observed in rats with HF after myocardial infarction surgery. Wire myograph studies were carried out in thoracic aorta rings in the presence and absence of PVAT. An anticontractile effect of PVAT was observed in the rings of the control rats in the presence (33%) or absence (11%) of endothelium. Moreover, this response was substantially reduced in animals with HF (5%), and acute type 1 angiotensin II receptor (AT1R) and type 2 angiotensin II receptor (AT2R) blockade restored the anticontractile effect of PVAT. In addition, the angiotensin-converting enzyme 1 (ACE1) activity (26%) and angiotensin II levels (51%), as well as the AT1R and AT2R gene expression, were enhanced in the PVAT of rats with HF. Associated with these alterations, HF-induced lower nitric oxide bioavailability, oxidative stress and whitening of the PVAT, which suggests changes in the secretory function of this tissue. The ACE1/angiotensin II/AT1R and AT2R axes are involved in thoracic aorta PVAT dysfunction in rats with HF. These results suggest PVAT as a target in the pathophysiology of vascular dysfunction in HF and provide new perspectives for the treatment of this syndrome. [ABSTRACT FROM AUTHOR]

Twenty years ago, the discovery of angiotensin-converting enzyme 2 (ACE2) was an important breakthrough dramatically enhancing our understanding of the renin-angiotensin system (RAS). The classical RAS is driven by its key enzyme ACE and is pivotal in the regulation of blood pressure and fluid homeostasis. More recently, it has been recognised that the protective RAS regulated by ACE2 counterbalances many of the deleterious effects of the classical RAS. Studies in murine models demonstrated that manipulating the protective RAS can dramatically alter many diseases including liver disease. Liver-specific overexpression of ACE2 in mice with liver fibrosis has proved to be highly effective in antagonising liver injury and fibrosis progression. Importantly, despite its highly protective role in disease pathogenesis, ACE2 is hijacked by SARS-CoV-2 as a cellular receptor to gain entry to alveolar epithelial cells, causing COVID-19, a severe respiratory disease in humans. COVID-19 is frequently life-threatening especially in elderly or people with other medical conditions. As an unprecedented number of COVID-19 patients have been affected globally, there is an urgent need to discover novel therapeutics targeting the interaction between the SARS-CoV-2 spike protein and ACE2. Understanding the role of ACE2 in physiology, pathobiology and as a cellular receptor for SARS-CoV-2 infection provides insight into potential new therapeutic strategies aiming to prevent SARS-CoV-2 infection related tissue injury. This review outlines the role of the RAS with a strong focus on ACE2-driven protective RAS in liver disease and provides therapeutic approaches to develop strategies to prevent SARS-CoV-2 infection in humans. [ABSTRACT FROM AUTHOR]

Acute Kidney Injury (AKI) comprises a rapidly developed renal failure and is associated with high mortality rates. The Renin-Angiotensin System (RAS) plays a pivotal role in AKI, as the over-active RAS axis exerts major deleterious effects in disease progression. In this sense, the conversion of Angiotensin II (Ang II) into Angiotensin-(1-7) (Ang-(1-7)) by the Angiotensin-converting enzyme 2 (ACE2) is of utmost importance to prevent worse clinical outcomes. Previous studies reported the beneficial effects of oral diminazene aceturate (DIZE) administration, an ACE2 activator, in renal diseases models. In the present study, we aimed to evaluate the therapeutic effects of DIZE administration in experimental AKI induced by gentamicin (GM) in rats. Our findings showed that treatment with DIZE improved renal function and tissue damage by increasing Ang-(1-7) and ACE2 activity, and reducing TNF-a. These results corroborate with a raising potential of ACE2 activation as a strategy for treating AKI. [ABSTRACT FROM AUTHOR]

In 2020 we are celebrating the 20th anniversary of the angiotensin-converting enzyme 2 (ACE2) discovery. This event was a landmark that shaped the way that we see the renin-angiotensin system (RAS) today. ACE2 is an important molecular hub that connects the RAS classical arm, formed mainly by the octapeptide angiotensin II (Ang II) and its receptor AT1, with the RAS alternative or protective arm, formed mainly by the heptapeptides Ang-(1-7) and alamandine, and their receptors, Mas and MrgD, respectively. In this work we reviewed classical and modern literature to describe how ACE2 is a critical component of the protective arm, particularly in the context of the cardiac function, coagulation homeostasis and immune system. We also review recent literature to present a critical view of the role of ACE2 and RAS in the SARS-CoV-2 pandemic. [ABSTRACT FROM AUTHOR]

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the global corona virus disease 2019 (COVID-19) pandemic enters host cells via a mechanism that includes binding to angiotensin converting enzyme (ACE) 2 (ACE2). Membrane-bound ACE2 is depleted as a result of this entry mechanism. The consequence is that the protective renin-angiotensin system (RAS), of which ACE2 is an essential component, is compromised through lack of production of the protective peptides angiotensin-(1-7) and angiotensin-(1-9), and therefore decreased stimulation of Mas (receptor Mas) and angiotensin AT2-receptors (AT2Rs), while angiotensin AT1-receptors (AT1Rs) are overstimulated due to less degradation of angiotensin II (Ang II) by ACE2. The protective RAS has numerous beneficial actions, including anti-inflammatory, anti-coagulative, anti-fibrotic effects along with endothelial and neural protection; opposite to the deleterious effects caused by heightened stimulation of angiotensin AT1R. Given that patients with severe COVID-19 exhibit an excessive immune response, endothelial dysfunction, increased clotting, thromboses and stroke, enhancing the activity of the protective RAS is likely beneficial. In this article, we discuss the evidence for a dysfunctional protective RAS in COVID and develop a rationale that the protective RAS imbalance in COVID-19 may be corrected by using AT2R agonists. We further review preclinical studies with AT2R agonists which suggest that AT2R stimulation may be therapeutically effective to treat COVID-19-induced disorders of various organ systems such as lung, vasculature, or the brain. Finally, we provide information on the design of a clinical trial in which patients with COVID-19 were treated with the AT2R agonist Compound 21 (C21). This trial has been completed, but results have not yet been reported. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin-angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme (ACE) is well-known for its role in blood pressure regulation via the renin-angiotensin aldosterone system (RAAS) but also functions in fertility, immunity, haematopoiesis and diseases such as obesity, fibrosis and Alzheimer's dementia. Like ACE, the human homologue ACE2 is also involved in blood pressure regulation and cleaves a range of substrates involved in different physiological processes. Importantly, it is the functional receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 responsible for the 2020, coronavirus infectious disease 2019 (COVID-19) pandemic. Understanding the interaction between SARS-CoV-2 and ACE2 is crucial for the design of therapies to combat this disease. This review provides a comparative analysis of methodologies and findings to describe how structural biology techniques like X-ray crystallography and cryo-electron microscopy have enabled remarkable discoveries into the structure-function relationship of ACE and ACE2. This, in turn, has enabled the development of ACE inhibitors for the treatment of cardiovascular disease and candidate therapies for the treatment of COVID-19. However, despite these advances the function of ACE homologues in non-human organisms is not yet fully understood. ACE homologues have been discovered in the tissues, body fluids and venom of species from diverse lineages and are known to have important functions in fertility, envenoming and insect-host defence mechanisms. We, therefore, further highlight the need for structural insight into insect and venom ACE homologues for the potential development of novel anti-venoms and insecticides. [ABSTRACT FROM AUTHOR]

Arachidonic acid can be metabolized in blood vessels by three primary enzymatic pathways; cyclooxygenase (COX), lipoxygenase (LO), and cytochrome P450 (CYP). These eicosanoid metabolites can influence endothelial and vascular smooth muscle cell function. COX metabolites can cause endothelium-dependent dilation or constriction. Prostaglandin I2 (PGI2) and thromboxane (TXA2) act on their respective receptors exerting opposing actions with regard to vascular tone and platelet aggregation. LO metabolites also influence vascular tone. The 12-LO metabolite 12S-hydroxyeicosatrienoic acid (12S-HETE) is a vasoconstrictor whereas the 15-LO metabolite 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA) is an endothelial-dependent hyperpolarizing factor (EDHF). CYP enzymes produce two types of eicosanoid products: EDHF vasodilator epoxyeicosatrienoic acids (EETs) and the vasoconstrictor 20-HETE. The less-studied cross-metabolites generated from arachidonic acid metabolism by multiple pathways can also impact vascular function. Likewise, COX, LO, and CYP vascular eicosanoids interact with paracrine and hormonal factors such as the renin-angiotensin system and endothelin-1 (ET-1) to maintain vascular homeostasis. Imbalances in endothelial and vascular smooth muscle cell COX, LO, and CYP metabolites in metabolic and cardiovascular diseases result in vascular dysfunction. Restoring the vascular balance of eicosanoids by genetic or pharmacological means can improve vascular function in metabolic and cardiovascular diseases. Nevertheless, future research is necessary to achieve a more complete understanding of how COX, LO, CYP, and cross-metabolites regulate vascular function in physiological and pathological states. [ABSTRACT FROM AUTHOR]

The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin-angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein-coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed. [ABSTRACT FROM AUTHOR]

The brain renin-angiotensin system (RAS) plays an important role in the regulation of autonomic and neuroendocrine functions, and maintains cardiovascular homeostasis. Ang-II is the major effector molecule of RAS and exerts most of its physiological functions, including blood pressure (BP) regulation, via activation of AT1 receptors. Dysregulation of brain RAS in the central nervous system results in increased Ang-II synthesis that leads to sympathetic outflow and hypertension. Brain angiotensin (Ang) converting enzyme-2 (ACE2) was discovered two decades ago as an RAS component, exhibiting a counter-regulatory role and opposing the adverse cardiovascular effects produced by Ang-II. Studies using synthetic compounds that can sustain the elevation of ACE2 activity or genetically overexpressed ACE2 in specific brain regions found various beneficial effects on cardiovascular function. More recently, ACE2 has been shown to play critical roles in neuro-inflammation, gut dysbiosis and the regulation of stress and anxiety-like behaviors. In the present review, we aim to highlight the anatomical locations and functional implication of brain ACE2 related to its BP regulation via modulation of the sympathetic nervous system and discuss the recent developments and future directions in the ACE2-mediated central cardiovascular regulation. [ABSTRACT FROM AUTHOR]

The apelinergic system is widely expressed and acts through autocrine and paracrine signaling to exert protective effects, including vasodilatory, metabolic, and inotropic effects on the cardiovascular (CV) system. The apelin pathway's dominant physiological role has delineated therapeutic implications for coronary artery disease, heart failure (HF), aortic aneurysm, pulmonary arterial hypertension (PAH), and transplant vasculopathy. Apelin peptides interact with the renin-angiotensin system (RAS) by promoting angiotensin converting enzyme 2 (ACE2) transcription leading to increased ACE2 protein and activity while also antagonizing the effects of angiotensin II (Ang II). Apelin modulation of the RAS by increasing ACE2 action is limited due to its rapid degradation by proteases, including ACE2, neprilysin (NEP), and kallikrein. Apelin peptides are hence tightly regulated in a negative feedback manner by ACE2. Plasma apelin levels are suppressed in pathological conditions, but its diagnostic and prognostic utility requires further clinical exploration. Enhancing the beneficial actions of apelin peptides and ACE2 axes while complementing existing pharmacological blockade of detrimental pathways is an exciting pathway for developing new therapies. In this review, we highlight the interaction between the apelin and ACE2 systems, discuss their pathophysiological roles and potential for treating a wide array of CV diseases (CVDs). [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is the most frequent type of epilepsy and is often refractory to pharmacological treatment. In this scenario, extensive research has identified components of the renin-angiotensin system (RAS) as potential therapeutic targets. Therefore, the aim of the present study was to evaluate the effects of long-term treatment with angiotensin-(1-7) [Ang-(1-7)] in male Wistar rats with TLE induced by pilocarpine (PILO). Rats with TLE were submitted to intracerebroventricular (icv) infusion of Ang-(1-7) (200 ng/kg/h) for 28 days, starting at the first spontaneous motor seizure (SMS). Body weight, food intake, and SMS were evaluated daily. Behavioral tests and hippocampal protein levels were also evaluated at the end of the treatment. Ang-(1-7) treatment reduced the frequency of SMS and attenuated low anxiety levels, increased locomotion/exploration, and reduced body weight gain that was induced by TLE. Moreover, Ang-(1-7) positively regulated the hippocampal levels of antioxidant protein catalase and antiapoptotic protein B-cell lymphoma 2 (Bcl-2), as well as mammalian target of rapamycin (mTOR) phosphorylation, which were reduced by TLE. The hippocampal up-regulation of angiotensin type 1 receptor induced by TLE was also attenuated by Ang-(1-7), while the Mas receptor (MasR) was down-regulated compared with epilepsy. These data show that Ang-(1-7) presents an antiepileptic effect, increasing neuroprotection markers and reducing SMS frequency, body weight, and behavior impairments found in TLE. Therefore, Ang-(1-7) is a promising coadjutant therapeutic option for the treatment of TLE. [ABSTRACT FROM AUTHOR]

Aldosterone, as a major product of renin-angiotensin-aldosterone system (RAAS), determines multiple pathophysiological processes in cardiovascular diseases. The excess inflammatory response is one of the key profiles in aldosterone-mediated cardiac remodeling. However, the potential mechanisms of aldosterone/inflammatory signaling were still not fully disclosed. The present study aimed to investigate whether TIR-domain-containing adapter-inducing interferon-ß (Trif) participated in the aldosterone-induced cardiac remodeling, and to explore potential molecular mechanisms. Trif knockout mice and their littermates were osmotically administrated with aldosterone (50 µg/kg per day) for 21 and 42 days. The cardiac structural analysis, functional parameters, and mitochondrial function were measured. Aldosterone dose- or time-dependently increased the levels of TRIF in primary mouse cardiomyocytes or mouse heart tissues. Trif deficiency protected against aldosterone-induced cardiac hypertrophy, fibrosis and dysfunction. Moreover, Trif deficiency also suppressed aldosterone-induced cardiac inflammatory response and mitochondrial injuries. Mechanistically, overexpression of cardiac microRNAs (miR)-34a reversed the cardiac benefits of Trif deficiency in aldosterone-treated mice. Taken together, Trif/miR-34a axis could provide a novel molecular mechanism for explaining aldosterone-induced cardiac hypertrophy, fibrosis and functional disorders. [ABSTRACT FROM AUTHOR]

The emergency of SARS-CoV-2 in China started a novel challenge to the scientific community. As the virus turns pandemic, scientists try to map the cellular mechanisms and pathways of SARS-CoV-2 related to the pathogenesis of Coronavirus Disease 2019 (Covid-19). After transmembrane angiotensin-converting enzyme 2 (ACE2) has been found to be SARS-CoV-2 receptor, we hypothesized an immune-hematological mechanism for Covid-19 based on renin-angiotensin system (RAS) imbalance to explain clinical, laboratory and imaging findings on disease course. We believe that exaggerated activation of ACE/Angiotensin II (Ang II)/Angiotensin Type 1 (AT1) receptor RAS axis in line with reduction of ACE2/Angiotensin-(1-7)/Mas receptor may exert a pivotal role in the pathogenesis of Covid-19. In this perspective, we discuss potential mechanisms and evidence on this hypothesis. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2) plays an essential role in maintaining the balance of the renin-angiotensin system and also serves as a receptor for the SARS-CoV-2, SARS-CoV, and HCoV-NL63. Following the recent outbreak of SARS-CoV-2 infection, there has been an urgent need to develop therapeutic interventions. ACE2 is a potential target for many treatment approaches for the SARS-CoV-2. With the help of bioinformatics, we have predicted several novel exons of the human ACE2 gene. The inclusion of novel exons located in the 5'UTR/intronic region in the mature transcript may remove the critical ACE2 residues responsible for the interaction with the receptor-binding domain (RBD) of SARS-CoV-2, thus preventing their binding and entry into the cell. Additionally, inclusion of a novel predicted exons located in the 3'UTR by alternative splicing may remove the C-terminal transmembrane domain of ACE2 and generate soluble ACE2 isoforms. Splice-switching antisense oligonucleotides (SSOs) have been employed effectively as a therapeutic strategy in several disease conditions. Alternative splicing of the ACE2 gene could similarly be modulated using SSOs to exclude critical domains required for the entry of SARS-CoV-2. Strategies can also be designed to deliver these SSOs directly to the lungs in order to minimize the damage caused by SARS-CoV-2 pathogenesis. [ABSTRACT FROM AUTHOR]

Adverse events during fetal life such as insufficient protein intake or elevated transfer of glucocorticoid to the fetus may impact cardiovascular and metabolic health later in adult life and are associated with increased incidence of type 2 diabetes, ischemic heart disease and hypertension. Several adverse factors converge and suppress the fetal renin-angiotensin-aldosterone system (RAAS). The aim of this review is to summarize data on the significance of RAAS for kidney development and adult hypertension. Genetic inactivation of RAAS in rodents at any step from angiotensinogen to angiotensin II (ANGII) type 1 receptor (AT1) receptors or pharmacologic inhibition leads to complex developmental injury to the kidneys that has also been observed in human case reports. Deletion of the 'protective' arm of RAAS, angiotensin converting enzyme (ACE) 2 (ACE-2) and G-protein coupled receptor for Angiotensin 1-7 (Mas) receptor does not reproduce the AT1 phenotype. The changes comprise fewer glomeruli, thinner cortex, dilated tubules, thicker arterioles and arteries, lack of vascular bundles, papillary atrophy, shorter capillary length and volume in cortex and medulla. Altered activity of systemic and local regulators of fetal-perinatal RAAS such as vitamin D and cyclooxygenase (COX)/prostaglandins are associated with similar injuries. ANGII-AT1 interaction drives podocyte and epithelial cell formation of vascular growth factors, notably vascular endothelial growth factor (VEGF) and angiopoietins (Angpts), which support late stages of glomerular and cortical capillary growth and medullary vascular bundle formation and patterning. RAAS-induced injury is associated with lower glomerular filtration rate (GFR), lower renal plasma flow, kidney fibrosis, up-regulation of sodium transporters, impaired sodium excretion and salt-sensitive hypertension. The renal component and salt sensitivity of programmed hypertension may impact dietary counseling and choice of pharmacological intervention to treat hypertension. [ABSTRACT FROM AUTHOR]

Alport syndrome is a rare genetic disease that results in disordered basement membrane type IV collagen resulting in occular and auditory defects as well of progressive kidney disease. Although no 'cure' currently exists, therapeutic blockade of the renin-angiotensin-aldosterone system can slow the progression to end-stage kidney disease (ESKD). Clinical trials for treatments in preventing chronic kidney disease have largely been negative over the last two decades until recent trials have shown positive cardiovascular and renal outcomes of sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with diabetes mellitus. Although marketed as medications for Type 2 diabetes, SGLT2 inhibitors have been found to have additional properties that are nephroprotective which makes them a potential candidate for treatment for those with other forms of progressive kidney disease. This review discusses the evidence for the use of SGLT2 inhibitors as a potential treatment in Alport syndrome that may slow the progression of chronic kidney disease and prevent patients reaching ESKD. [ABSTRACT FROM AUTHOR]

Kir5.1 (encoded by the Kcnj16 gene) is an inwardly rectifying K+ (Kir) channel highly expressed in the aldosterone-sensitive distal nephron of the kidney, where it forms a functional channel with Kir4.1. Kir4.1/Kir5.1 channels are responsible for setting the transepithelial voltage in the distal nephron and collecting ducts and are thereby major determinants of fluid and electrolyte distribution. These channels contribute to renal blood pressure control and have been implicated in salt-sensitive hypertension. However, mechanisms pertaining to the impact of K ir4.1/Kir5.1-mediated K+ transport on the renin-angiotensin-aldosterone system (RAAS) remain unclear. Herein, we utilized a knockout of Kcnj16 in the Dahl salt-sensitive rat (SSKcnj16-/-) to investigate the relationship between Kir5.1 and RAAS balance and function in the sensitivity of blood pressure to the dietary Na+/K+ ratio. The knockout of Kcnj16 caused substantial elevations in plasma RAAS hormones (aldosterone and angiotensin peptides) and altered the RAAS response to changing the dietary Na+/K+ ratio. Blocking aldosterone with spironolactone caused rapid mortality in SSKcnj16-/- rats. Supplementation of the diet with high K+ was protective against mortality resulting from aldosterone-mediated mechanisms. Captopril and losartan treatment had no effect on the survival of SSKcnj16-/- rats. However, neither of these drugs prevented mortality of SSKcnj16-/- rats when switched to high Na+ diet. These studies revealed that the knockout of Kcnj16 markedly altered RAAS regulation and function, suggesting Kir5.1 as a key regulator of the RAAS, particularly when exposed to changes in dietary sodium and potassium content. [ABSTRACT FROM AUTHOR]

The underlying mechanism by which amassing of white adipose tissue in obesity regulates sympathetic nerve system (SNS) drive to the tissues responsible for glucose disposal, and causes insulin resistance (IR), remains unknown. We tested the hypothesis that high-fat (HF) feeding increases afferent impulses from white adipose tissue that reflexively elevate efferent nerve activity to skeletal muscle (SM) and adipose tissue to impair their local glucose uptake. We also investigated how salt-intake can enhance IR. HF-fed rats received a normal salt (0.4%) or high salt (4%) diet for 3 weeks. High-salt intake in HF fed rats decreased insulin-stimulated 2-deoxyglucose uptake by over 30% in white adipose tissue and SM, exacerbated inflammation, and impaired their insulin signaling and glucose transporter 4 (Glut4) trafficking. Dietary salt in HF fed rats also increased the activity of the adipose-cerebral-muscle renin-angiotensin system (RAS) axes, SNS, and reactive oxygen species (ROS). Insulin sensitivity was reduced by 32% in HF rats during high-salt intake, but was improved by over 62% by interruption of central RAS and SNS drive, and by over 45% by denervation or deafferentation of epididymal fat (all P<0.05). Our study suggest that a HF diet engages a sympathetic reflex from the white adipose tissue that activates adipose-cerebral-muscle RAS/ROS axes and coordinates a reduction in peripheral glucose uptake. These are all enhanced by salt-loading. These findings provide new insight into the role of a reflex initiated in adipose tissue in the regulation of glucose homeostasis during HF feeding that could lead to new therapeutic approaches to IR. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is present in the gastrointestinal (GI) tract but remains to be fully characterized, particularly in man. The duodenum plays a role in both the upper and lower GI regulation, as well as in distant organs. The present study investigates the presence and functional potential of RAS in the human duodenal mucosa of healthy individuals. Endoscopically acquired mucosal biopsies from healthy volunteers were examined using western blot, immunohistochemistry, and ELISA. Functionality was examined by using Ussing chambers and recording duodenal transmucosal potential difference (PD) and motility in vivo. Angiotensinogen, Angiotensin II (AngII) and its receptors (AT1R, AT2R) as well as to the RAS associated enzymes renin, ACE, and neprylisin were detected in all samples of duodenal mucosa. Migrating motility complex induced elevations of transmucosal PD were significantly larger after per-oral administration of the AT1R receptor antagonist candesartan. Fasting duodenal motility per se was not influenced by candesartan. The epithelial current produced by duodenal mucosae mounted in Ussing chambers increased significantly after addition of AngII to specimens where the AT1R was blocked using losartan. The epithelial current also increased after addition of the AT2R-selective agonist C21. Immunostaining and pharmacological data demonstrate the presence of a local RAS in the human duodenal mucosa with capacity to influence epithelial ion transport by way of particulary the AT2R. [ABSTRACT FROM AUTHOR]

Distal nephron of the kidney plays key roles in fluid volume and electrolyte homeostasis by tightly regulating reabsorption and excretion of Na+, K+, and Cl-. Studies to date demonstrate the detailed electrolyte transport mechanisms in principal cells of the cortical collecting duct, and their regulation by renin-angiotensin-aldosterone system (RAAS). In recent years, however, accumulating data indicate that intercalated cells, another cell type that is present in the cortical collecting duct, also play active roles in the regulation of blood pressure. Notably, pendrin in ß-intercalated cells not only controls acid/base homeostasis, but is also one of the key components controlling salt and K+ transport in distal nephron. We have recently shown that pendrin is regulated by the co-ordinated action of angiotensin II (AngII) and aldosterone, and at the downstream of AngII, mammalian target of rapamycin (mTOR) signaling regulates pendrin through inhibiting the kinase unc51-like-kinase 1 and promoting dephosphorylation of mineralocorticoid receptor (MR). In this review, we summarize recent advances in the current knowledge on the salt transport mechanisms in the cortical collecting duct, and their regulation by the RAAS. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is highly conserved, and components of the RAS are present in all vertebrates to some degree. Although the RAS has been studied since the discovery of renin, its biological role continues to broaden with the identification and characterization of new peptides. The evolutionarily distant zebrafish is a remarkable model for studying the kidney due to its genetic tractability and accessibility for in vivo imaging. The zebrafish pronephros is an especially useful kidney model due to its structural simplicity yet complex functionality, including capacity for glomerular and tubular filtration. Both the pronephros and mesonephros contain renin-expressing perivascular cells, which respond to RAS inhibition, making the zebrafish an excellent model for studying the RAS. This review summarizes the physiological and genetic tools currently available for studying the zebrafish kidney with regards to functionality of the RAS, using novel imaging techniques such as SPIM microscopy coupled with targeted single cell ablation and synthesis of vasoactive RAS peptides. [ABSTRACT FROM AUTHOR]

Objective: Low sodium intake is paradoxically associated with adverse cardiovascular outcomes in individuals with type 2 diabetes mellitus (T2D), possibly from renin-angiotensin-aldosterone system (RAAS) activation, leading to endothelial dysfunction. In the present study, we investigated the associations between habitual sodium intake and RAAS blockade on endothelial function by measuring circulating microparticles (MPs) in individuals with T2D. Methods: We conducted a prospective, cross-sectional study in 74 individuals with T2D. Habitual dietary sodium intake was estimated by using the mean of three corrected 24-h urine sodium excretion measurements (24hUNa). MP subtypes in platelet-free plasma were quantitated using flow cytometry. Results: No associations between 24hUNa with levels of endothelial MPs were observed. Instead, a trend toward higher diabetes related CD36+/CD235a+ MP levels was associated with lower 24hUNa (rho = -0.23, P=0.05). When stratified according to tertiles of 24hUNa, platelet-derived CD42b+/CD41+ and CD42+/CD41+/Annexin V+ MPs were higher in the lowest tertile (24hUNa < 157 mmol/24 h) (P=0.02 respectively). Despite RAAS blockade being associated with lower levels of most MP subsets, it was not associated with lower MPs, in the setting of low sodium intake. Conclusion: Lower sodium intake is associated with higher circulating procoagulant MPs, but not with evidence of endothelial dysfunction in individuals with T2D. [ABSTRACT FROM AUTHOR]

Overactivation of the renin-angiotensin (Ang) system (RAS) increases the classical arm (Ang-converting enzyme (ACE)/Ang II/Ang type 1 receptor (AT1R)) to the detriment of the protective arm (ACE2/Ang 1-7/Mas receptor (MasR)). The components of the RAS are present locally in white adipose tissue (WAT) and skeletal muscle, which act co-operatively, through specific mediators, in response to pathophysiological changes. In WAT, up-regulation of the classical arm promotes lipogenesis and reduces lipolysis and adipogenesis, leading to adipocyte hypertrophy and lipid storage, which are related to insulin resistance and increased inflammation. In skeletal muscle, the classical arm promotes protein degradation and increases the inflammatory status and oxidative stress, leading to muscle wasting. Conversely, the protective arm plays a counter-regulatory role by opposing the effect of Ang II. The accumulation of adipose tissue and muscle mass loss is associated with a higher risk of morbidity and mortality, which could be related, in part, to overactivation of the RAS. On the other hand, exercise training (ExT) shifts the balance of the RAS towards the protective arm, promoting the inhibition of the classical arm in parallel with the stimulation of the protective arm. Thus, fat mobilization and maintenance of muscle mass and function are facilitated. However, the mechanisms underlying exercise-induced changes in the RAS remain unclear. In this review, we present the RAS as a key mechanism of WAT and skeletal muscle metabolic dysfunction. Furthermore, we discuss the interaction between the RAS and exercise and the possible underlying mechanisms of the health-related aspects of ExT. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is widely recognized as one of the most important vasoactive hormonal systems in the physiological regulation of blood pressure and the development of hypertension. This recognition is derived from, and supported by, extensive molecular, cellular, genetic, and pharmacological studies on the circulating (tissue-to-tissue), paracrine (cell-to-cell), and intracrine (intracellular, mitochondrial, nuclear) RAS during last several decades. Now, it is widely accepted that circulating and local RAS may act independently or interactively, to regulate sympathetic activity, systemic and renal hemodynamics, body salt and fluid balance, and blood pressure homeostasis. However, there remains continuous debate with respect to the specific sources of intratubular and intracellular RAS in the kidney and other tissues, the relative contributions of the circulating RAS to intratubular and intracellular RAS, and the roles of intratubular compared with intracellular RAS to the normal control of blood pressure or the development of angiotensin II (ANG II)-dependent hypertension. Based on a lecture given at the recent XI International Symposium on Vasoactive Peptides held in Horizonte, Brazil, this article reviews recent studies using mouse models with global, kidney- or proximal tubule-specific overexpression (knockin) or deletion (knockout) of components of the RAS or its receptors. Although much knowledge has been gained from cell- and tissue-specific transgenic or knockout models, a unifying and integrative approach is now required to better understand how the circulating and local intratubular/ intracellular RAS act independently, or with other vasoactive systems, to regulate blood pressure, cardiovascular and kidney function. [ABSTRACT FROM AUTHOR]

The existence of a so-called brain renin-angiotensin system (RAS) is controversial. Given the presence of the blood-brain barrier, angiotensin generation in the brain, if occurring, should depend on local synthesis of renin and angiotensinogen. Yet, although initially brain-selective expression of intracellular renin was reported, data in intracellular renin knockout animals argue against a role for this renin in angiotensin generation. Moreover, renin levels in brain tissue at most represented renin in trapped blood. Additionally, in neurogenic hypertension brain prorenin up-regulation has been claimed, which would generate angiotensin following its binding to the (pro)renin receptor. However, recent studies reported no evidence for prorenin expression in the brain, nor for its selective up-regulation in neurogenic hypertension and the (pro)renin receptor rather displays RAS-unrelated functions. Finally, although angiotensinogen mRNA is detectable in the brain, brain angiotensinogen protein levels are low and even these low levels might be an overestimation due to assay artefacts. Taken together, independent angiotensin generation in the brain is unlikely. Indeed, brain angiotensin levels are extremely low, with angiotensin (Ang) I levels corresponding to the small amounts of Ang I in trapped blood plasma and Ang II levels at most representing Ang II bound to (vascular) brain Ang II type 1 receptors. This review concludes with a unifying concept proposing the blood origin of angiotensin in the brain, possibly resulting in increased levels following blood-brain barrier disruption (e.g. due to hypertension) and suggesting that interfering with either intracellular renin or the (pro)renin receptor has consequences in an RAS-independent manner. [ABSTRACT FROM AUTHOR]

The development of de novo albuminuria during chronic renin-angiotensin system (RAS) suppression is a clinical entity that remains poorly recognized in the biomedical literature. It represents a clear increment in global cardiovascular (CV) and renal risk that cannot be counteracted by RAS suppression. Although not specifically considered, it is clear that this entity is present in most published and ongoing trials dealing with the different forms of CV and renal disease. In this review, we focus on the mechanisms promoting albuminuria and the predictors and new markers of de novo albuminuria, as well as the potential treatment options to counteract the excretion of albumin. The increase in risk that accompanies de novo albuminuria supports the search for early markers and predictors that will allow practising physicians to assess and prevent the development of de novo albuminuria in their patients. [ABSTRACT FROM AUTHOR]

ARNI [dual AT1 (angiotensin II type 1) receptor-neprilysin inhibition] exerts beneficial effects on blood pressure and kidney function in heart failure, compared with ARB (AT1 receptor blockade) alone. We hypothesized that ARNI improves cardiac and kidney parameters in diabetic TGR(mREN2)27 rats, an angiotensin II-dependent hypertension model. Rats were made diabetic with streptozotocin for 5 or 12 weeks. In the final 3 weeks, rats were treated with vehicle, irbesartan (ARB) or irbesartan+thiorphan (ARNI). Blood pressure, measured by telemetry in the 5-week group, was lowered identically by ARB and ARNI. The heart weight/tibia length ratio in 12-week diabetic animals was lower after ARNI compared with after ARB. Proteinuria and albuminuria were observed from 8 weeks of diabetes onwards. ARNI reduced proteinuria more strongly than ARB, and a similar trend was seen for albuminuria. Kidneys of ARNI-treated animals showed less severe segmental glomerulosclerosis than those of ARB-treated animals. After 12 weeks, no differences between ARNI- and ARB-treated animals were found regarding diuresis, natriuresis, plasma endothelin-1, vascular reactivity (acetylcholine response) or kidney sodium transporters. Only ARNI-treated rats displayed endothelin type B receptor-mediated vasodilation. In conclusion, ARNI reduces proteinuria, glomerulosclerosis and heart weight in diabetic TGR(mREN2)27 rats more strongly than does ARB, and this occurs independently of blood pressure. [ABSTRACT FROM AUTHOR]

Severe hypertension destroys eyesight. The RAS (renin-angiotensin system) may contribute to this. This study relied on an established angiotensin, AngII (angiotensin II)-elevated dTGR (double-transgenic rat) model and same-background SD (Sprague–Dawley) rat controls. In dTGRs, plasma levels of AngII were increased. We determined the general retinal phenotype and observed degeneration of ganglion cells that we defined as vascular degeneration. We also inspected relevant gene expression and lastly observed alterations in the outer blood-retinal barrier. We found that both scotopic a-wave and b-wave as well as oscillatory potential amplitude were significantly decreased in dTGRs, compared with SD rat controls. However, the b/a-wave ratio remained unchanged. Fluorescence angiography of the peripheral retina indicated that exudates, or fluorescein leakage, from peripheral vessels were increased in dTGRs compared with controls. Immunohistological analysis of blood vessels in retina whole-mount preparations showed structural alterations in the retina of dTGRs. We then determined the general retinal phenotype. We observed the degeneration of ganglion cells, defined vascular degenerations and finally found differential expression of RAS-related genes and angiogenic genes. We found the expression of both human angiotensinogen and human renin in the hypertensive retina. Although the renin gene expression was not altered, the AngII levels in the retina were increased 4-fold in the dTGR retina compared with that in SD rats, a finding with mechanistic implications. We suggest that alterations in the outer blood–retinal barrier could foster an area of visual-related research based on our findings. Finally, we introduce the dTGR model of retinal disease. [ABSTRACT FROM AUTHOR]