The aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e. ANG II type 1 and type 2 (AT1 and AT2) and Mas receptors] were assessed in TG7371 transgene-positive and in HanSD rats. We found that male TG7371 transgene-positive rats exhibited significantly elevated plasma, kidney, heart and lung ANG 1-7 concentrations as compared with control male HanSD rats; by contrast, there was no significant difference in ANG II concentrations and no significant differences in mRNA expression of AT1, AT2 and Mas receptors. In addition, we found that in male TG7371 transgene-positive rats blood pressure was lower than in male HanSD rats. These data indicate that the balance between the classical arm and the alternative arm of the RAS was in male TGR7371 transgene-positive rats markedly shifted in favor of the latter. In conclusion, TG7371 transgene-positive rats represent a new powerful tool to study the long-term role of the alternative arm of the RAS in the pathophysiology and potentially in the treatment of cardio-renal diseases.

• MeSH
• Angiotensin I * metabolism   MeSH
• Angiotensin II * MeSH
• Cardiovascular Diseases metabolism   genetics   MeSH
• Blood Pressure physiology   MeSH
• Rats MeSH
• Kidney metabolism   MeSH
• Kidney Diseases metabolism   genetics   MeSH
• Peptide Fragments * metabolism   MeSH
• Rats, Sprague-Dawley * MeSH
• Rats, Transgenic * MeSH
• Proto-Oncogene Mas MeSH
• Receptor, Angiotensin, Type 1 genetics   metabolism   MeSH
• Receptors, G-Protein-Coupled genetics   metabolism   MeSH
• Recombinant Fusion Proteins metabolism   MeSH
• Renin-Angiotensin System * physiology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The safety profile of venom immunotherapy (VIT) is a relevant issue, and considerable differences have been reported in the safety and efficacy of this treatment modality. The primary aim of this study was to evaluate the safety of angiotensin-converting enzyme inhibitors and ß-blockers during VIT. In a second analysis, we evaluated data on premedication and venom preparations and their association with systemic adverse events (AEs) during the up-dosing phase and the first year of the maintenance phase, as well as the outcome of field stings and sting challenges. METHODS: Ours was an open, prospective, observational, multicenter study that recruited 1425 patients, of whom 1342 underwent VIT. RESULTS: Premedication with oral antihistamines was taken by 52.1% of patients during up-dosing and 19.7% of patients during the maintenance phase. Antihistamines had no effect on the frequency of systemic AEs (P=.11), although large local reactions (LLRs) were less frequent (OR, 0.74; 95%CI, 0.58-0.96; P=.02). Aqueous preparations were preferred for up-dosing (73.0%), and depot preparations were used for the maintenance phase (64.5%). The type of venom preparation had no influence on the frequency of systemic AEs or on the effectiveness of VIT (P=.26 and P=.80, respectively), while LLRs were less frequent with depot preparations (P<.001). CONCLUSIONS: Pretreatment with oral antihistamines during VIT significantly reduces the frequency of LLRs but not systemic AEs. All venom preparations were equally effective and did not differ in terms of the frequency of systemic AEs.

• MeSH
• Allergens immunology   administration & dosage   MeSH
• Histamine Antagonists therapeutic use   MeSH
• Adrenergic beta-Antagonists therapeutic use   MeSH
• Desensitization, Immunologic * methods   adverse effects   MeSH
• Child MeSH
• Adult MeSH
• Angiotensin-Converting Enzyme Inhibitors therapeutic use   adverse effects   MeSH
• Insect Bites and Stings immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Prospective Studies MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Venoms immunology   adverse effects   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

munologicky zprostředkované postižení ledvin – IgA nefropatie je nejčastější glomerulonefritidou. Onemocnění postihuje často mladé lidi a je spojeno s vysokým rizikem progrese do chronického selhání ledvin vyžadujícího náhradu funkce ledvin. Donedávna byly jedinou možností léčby inhibice systému renin-angiotenzin a systémové kortikoidy s nejistým účinkem a závažnými nežádoucími účinky. Možnosti podpůrné léčby se v posledních letech rozšířily o inhibitory sodíko-glukozového kotransportéru typu 2 v proximálním tubulu (sodium-glucose cotransporter, 2SGLT2) a duálního antagonistu receptoru AT1 pro angiotenzin II a receptoru pro endotelin 1 (ETA) - sparsentan a budesonid s cíleným uvolňováním v ileu (Nefecon), který by měl nahradit systémové kortikoidy. Další léky pravděpodobně brzy úspěšně projdou klinickým hodnocením. Recentní pokroky v léčbě by se měly projevit i významným zlepšením dlouhodobé prognózy nemocných.

IgA nephropathy is the most common glomerulonephritis. The disease often affects young people and is associated with a high risk of progression to chronic renal failure requiring renal function replacement. Until recently, inhibition of the renin-angiotensin system and systemic corticosteroids were the only treatment options, with uncertain effect and serious side effects. In recent years, supportive treatment options have expanded to include inhibitors of the sodium-glucose cotransporter type 2 in the proximal tubule (SGLT2) and the dual AT1 receptor for angiotensin II and endothelin 1 receptor (ETA) antagonists sparsentan and budesonide with targeted release in the ileum (Nefecon) to replace systemic corticosteroids. Other drugs are likely to undergo successful clinical trials soon. Recent advances in treatment should also result in a significant improvement in the long-term prognosis of patients.

Se zvyšujícím se počtem diabetiků v populaci dochází také ke zvýšení mikrovaskulárních a makrovaskulárních komplikací. Poškození ledvin představuje jednu z hlavních příčin mortality u pacientů s diabetem. Klasifikace diabetické nefropatie je založena na hodnotě glomerulární filtrace a stupni albuminurie a rozděluje pacienty do tříd podle mortalitního rizika. Léčba pacientů je založena na datech z velkých multicentrických studií, které prokázaly kardiovaskulární benefit zejména při používání gliflozinů. Proto glifloziny a statiny společně s metforminem patří mezi léky první volby u pacientů s diabetem mellitem 2. typu a renálním postižením. Komplexní péče o tyto nemocné by současně měla zahrnovat pravidelné dieto- logické konzultace, fyzickou aktivitu a psychologickou podporu. Odlišná situace je zatím u pacientů s diabetem mellitem 1. typu. Glifloziny se u těchto nemocných nedoporučují používat. Zde základem farmakoterapie zůstávají ACEi nebo sar- tany a současně dostatečná kompenzace diabetu. V pokročilých stadiích je důležité odesílat pacienty včas ke specialistům k posouzení transplantační léčby.

With the increasing number of diabetics in the population, there is also a rise in both microvascular and macrovascular complications. Kidney damage represents one of the leading causes of mortality in patients with diabetes. The classification of diabetic nephropathy is based on the glomerular filtration rate and the degree of albuminuria, categorizing patients into risk groups according to their mortality risk. The treatment of these patients is based on data from large multicenter studies, which have demonstrated cardiovascular benefits, particularly with the use of gliflozins. Therefore, gliflozins and statins, together with metformin, are among the first-line treatment options for patients with type 2 diabetes mellitus and renal impairment. Comprehensive care for these patients should also include regular dietary consultations, physical activity, and psychological support. The situation is different for patients with type 1 diabetes mellitus, where the use of gliflozins is not recommended. In this group, the cornerstone of pharmacotherapy remains ACE inhibitors or sartans, along with adequate diabetes management. In advanced stages of the disease, it is crucial to refer patients to specialists in a timely manner for the evaluation of transplantation therapy.

• MeSH
• Angiotensin II Type 1 Receptor Blockers administration & dosage   pharmacology   therapeutic use   MeSH
• Diabetes Mellitus * diagnosis   therapy   MeSH
• Diabetic Nephropathies diagnosis   drug therapy   prevention & control   MeSH
• Sodium-Glucose Transporter 2 Inhibitors administration & dosage   pharmacology   therapeutic use   MeSH
• Diabetes Complications prevention & control   therapy   MeSH
• Humans MeSH
• Kidney Transplantation MeSH
• Pancreas Transplantation MeSH
• Check Tag
• Humans MeSH

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that emerged in late 2019 and rapidly spread worldwide, causing the COVID-19 pandemic. The spike glycoprotein (S protein) plays a crucial role in viral target recognition and entry by interacting with angiotensin, converting enzyme 2 (ACE2), the functional receptor for the virus, via its receptor binding domain (RBD). The RBD availability for this interaction can be influenced by external factors, such as fatty acids. Linoleic acid (LA), a free fatty acid, has been shown to bind the S protein, modulating the viral infection by reducing initial target recognition. LA interacts with the fatty acid binding pocket (FABP), a potential drug target against SARS-CoV-2. In this study, we aimed to exploit the FABP as a drug target by performing a docking-based virtual screening with a library of commercially available, drug-like compounds. The virtual hits identified were then assessed in in vitro assays for the inhibition of the virus-host interaction and cytotoxicity. Binding assays targeting the spike-ACE2 interaction identified multiple compounds with inhibitory activity and low cytotoxicity.

• MeSH
• Angiotensin-Converting Enzyme 2 * metabolism   chemistry   MeSH
• Antiviral Agents pharmacology   chemistry   metabolism   MeSH
• COVID-19 virology   metabolism   MeSH
• COVID-19 Drug Treatment MeSH
• Spike Glycoprotein, Coronavirus * metabolism   chemistry   MeSH
• Linoleic Acid metabolism   chemistry   MeSH
• Humans MeSH
• Fatty Acid-Binding Proteins metabolism   MeSH
• SARS-CoV-2 * metabolism   drug effects   MeSH
• Molecular Docking Simulation * MeSH
• Protein Binding * MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

There is little data regarding the impact of renin-angiotensin system (RAS) gene polymorphisms on tuberculosis. The current study designed to survey the possible association between RAS polymorphisms and the risk of pulmonary tuberculosis (PTB) in a sample of the southeast Iranian population. This case-control study was done on 170 PTB patients and 170 healthy subjects. The AGT rs699 C>T, ACE rs4341 C>G and AT1R rs5186 C>A variants were genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and ACE rs4646994 (287bp I/D) variant by PCR method. Regarding AT1R rs5186 A>C polymorphism, the findings revealed that AC genotype and C allele significantly decreased the risk of PTB (OR=0.39, 95% CI=0.22-0.67, p=0.001, and OR=0.53, 95% CI=0.25-0.72, p=0.002, C vs. A, respectively). The TC genotype and C allele of AGT rs699 T>C significantly associated with decreased the risk of PTB (OR=0.45, 95% CI=0.28-0.74, p=0.002, TC vs. TT and OR=0.51, 95% CI=0.32-0.80, p=0.005, C vs. T, respectively). The ID genotype of ACE 287bp I/D significantly increased the risk of PTB (OR=1.88, 95% CI=1.12-3.17, p=0.017). Our finding did not support an association between ACE rs4341 C>G variant and the risk of PTB. In summary, the findings revealed an association between AT1R rs5186 A>C, AGT rs699 T>C and ACE 287bp I/D polymorphisms and the risk of PTB in a sample of the southeast Iranian population. Further investigation with higher sample sizes and diverse ethnicities are required to confirm our findings.

• MeSH
• Peptidyl-Dipeptidase A * genetics   MeSH
• Angiotensinogen genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• Humans MeSH
• Tuberculosis, Pulmonary * genetics   MeSH
• Polymorphism, Genetic MeSH
• Receptor, Angiotensin, Type 1 genetics   MeSH
• Case-Control Studies MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Iran MeSH

• MeSH
• Medication Adherence MeSH
• Antihypertensive Agents administration & dosage   therapeutic use   MeSH
• Calcium Channel Blockers administration & dosage   pharmacology   therapeutic use   MeSH
• Angiotensin II Type 1 Receptor Blockers administration & dosage   pharmacology   therapeutic use   MeSH
• Drug Combinations MeSH
• Hypertension * diagnosis   drug therapy   prevention & control   MeSH
• Angiotensin-Converting Enzyme Inhibitors administration & dosage   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Secondary Prevention MeSH
• Check Tag
• Humans MeSH

Léčba chronického srdečního selhání (CHSS) je vždy komplexní a zahrnuje farmakologické i nefarmakologické postupy. U mnoha pacientů však srdeční selhání progreduje do fáze pokročilého srdečního selhání, která je charakterizována perzistencí symptomů navzdory maximální terapii. Základem léčby pacientů se srdečním selháním s redukovanou ejekční frakcí (HFrEF) jsou tyto pilíře lékových skupin: inhibitory angiotenzin konvertujícího enzymu (ACEi)), duální inhibitor receptoru 1 pro angiotenzin II a neprilysinu (ARNI), betablokátory (BB), blokátory mineralokortikoidních receptorů (MRA) a inhibitory sodíko-glukozového kontransportéru 2 (SGLT2, glifloziny), které mají mortalitní data z velkých randomizovaných klinických studií. Doporučované je jejich včasné nasazení a rychlá uptitrace do maximální tolerované dávky. SGLT2i jsou navíc vhodné u všech pacientů se srdečním selháním bez ohledu na hodnotu ejekční frakce a jsou nyní doporučovány i pro léčbu pacientů se srdečním selháním s mírně redukovanou ejekční frakcí (HFmrEF) a zachovalou ejekční frakcí (HFpEF). Jako důležitá se též ukázala léčba komorbidit, a to zejména léčba anémie, kde své pevné místo má již intravenózní podání karboxymaltózy železa (FCM). Pacienti s diabetes mellitus II. typu a chronickým onemocněním ledvin mohou profitovat z léčby finerenonem. U pacientů s geneticky prokázanou hereditární formou srdeční transthyretinové amyloidózy a u pacientů s wild-type formou srdeční transthyretinové amyloidózy je doporučován tafamidis.

The treatment of chronic heart failure is always complex and includes both pharmacological and non-pharmacological procedures. However, the disease progresses to the end-stage of advanced heart failure in many patients, which is characterized by the persistence of symptoms despite maximal therapy. The basis of the treatment of patients with heart failure with reduced ejection fraction (HFrEF) are 4 pillars of drug groups: Angiotensin Receptor-Neprilysin Inhibitor (ARNI)/ Angiotensin-Converting Enzyme Inhibitors (ACEi), Beta blockers (BB), Mineralocorticoid receptor antagonist (MRA) and Sodium-glucose cotransporter-2 inhibitors (SGLT2i), which have mortality data from large randomized clinical trials. Their early use and rapid uptitration to the maximum tolerated dose is recommended. In addition, Sodium-glucose cotransporter-2 inhibitors SGLT2i are suitable for all heart failure patients regardless of ejection fraction value, and are also recommended for the treatment of Heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) patients. The treatment of comorbidities is also important, especially the treatment of anemia, where intravenous administration of iron carboxymaltose (FCM) already has its place. Patients with diabetes mellitus II. type and chronic kidney disease can benefit from treatment with finerenone. Tafamidis is recommended for patients with a genetically proven hereditary form of cardiac transthyretin amyloidosis and for patients with a wild-type form of cardiac transthyretin amyloidosis.

• MeSH
• Cardiovascular Agents * classification   therapeutic use   MeSH
• Clinical Studies as Topic MeSH
• Humans MeSH
• Heart Failure * drug therapy   classification   prevention & control   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Abdominal aortic aneurysms (AAA) result from maladaptive remodeling of the vascular wall and reduces structural integrity. Angiotensin II (AngII) infusion has become a standard laboratory model for studying AAA initiation and progression. We determined the different vasoactive responses of various mouse arteries to Ang II. Ex vivo isometric tension analysis was conducted on 18-week-old male C57BL/6 mice (n = 4) brachiocephalic arteries (BC), iliac arteries (IL), and abdominal (AA) and thoracic aorta (TA). Arterial rings were mounted between organ hooks, gently stretched and an AngII dose response was performed. Rings were placed in 4% paraformaldehyde for immunohistochemistry analysis to quantify peptide expression of angiotensin type 1 (AT1R) and 2 receptors (AT2R) in the endothelium, media, and adventitia. Results from this study demonstrated vasoconstriction responses in IL were significantly higher at all AngII doses when compared to BC, and TA and AA responses (maximum constriction-IL: 68.64 ± 5.47% vs. BC: 1.96 ± 1.00%; TA: 3.13 ± 0.16% and AA: 2.75 ± 1.77%, p < 0.0001). Expression of AT1R was highest in the endothelium of IL (p < 0.05) and in the media and (p < 0.05) adventitia (p < 0.05) of AA. In contrast, AT2R expression was highest in endothelium (p < 0.05), media (p < 0.01, p < 0.05) and adventitia of TA. These results suggest that mouse arteries display different vasoactive responses to AngII, and the exaggerated response in IL arteries may play a role during AAA development.

• MeSH
• Aortic Aneurysm, Abdominal * chemically induced   MeSH
• Angiotensin I MeSH
• Angiotensin II pharmacology   MeSH
• Aortic Aneurysm * MeSH
• Iliac Artery MeSH
• Arteries MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Peptide Hormones * MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Angiotensin-converting enzyme 2 (ACE2), one of the key enzymes of the renin-angiotensin system (RAS), plays an important role in SARS-CoV-2 infection by functioning as a virus receptor. Angiotensin peptides Ang I and Ang II, the substrates of ACE2, can modulate the binding of SARS-CoV-2 Spike protein to the ACE2 receptor. In the present work, we found that co incubation of HEK-ACE2 and Vero E6 cells with the SARS-CoV-2 Spike pseudovirus (PVP) resulted in stimulation of the virus entry at low and high micromolar concentrations of Ang I and Ang II, respectively. The potency of Ang I and Ang II stimulation of virus entry corresponds to their binding affinity to ACE2 catalytic pocket with 10 times higher efficiency of Ang II. The Ang II induced mild increase of PVP infectivity at 20 microM; while at 100 microM the increase (129.74+/-3.99 %) was highly significant (p<0.001). Since the angiotensin peptides act in HEK ACE2 cells without the involvement of angiotensin type I receptors, we hypothesize that there is a steric interaction between the catalytic pocket of the ACE2 enzyme and the SARS-CoV-2 S1 binding domain. Oversaturation of the ACE2 with their angiotensin substrate might result in increased binding and entry of the SARS-CoV-2. In addition, the analysis of angiotensin peptides metabolism showed decreased ACE2 and increased ACE activity upon SARS-CoV-2 action. These effects should be taken into consideration in COVID-19 patients suffering from comorbidities such as the over-activated renin-angiotensin system as a mechanism potentially influencing the SARS-CoV-2 invasion into recipient cells.

• MeSH
• Angiotensin I metabolism   pharmacology   MeSH
• Angiotensin II metabolism   MeSH
• Peptidyl-Dipeptidase A metabolism   MeSH
• Angiotensin-Converting Enzyme 2 metabolism   MeSH
• COVID-19 * MeSH
• Spike Glycoprotein, Coronavirus * MeSH
• Angiotensin-Converting Enzyme Inhibitors MeSH
• Humans MeSH
• Renin-Angiotensin System * MeSH
• SARS-CoV-2 metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH