Higher Angiotensin II type 1 receptor (AT1R) levels and activity in the post-mortem brains of older persons with Alzheimer's disease

Aging is a key risk factor in Alzheimer's dementia (AD) development and progression. The primary dementia-protective benefits of Angiotensin II subtype 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, a brain-specific renin-angiotensin system (b-RAS) exists, which can be altered by AT1R blockers. Brain RAS acts mainly through three angiotensin receptors: AT1R, AT2R, and AT4R. Changes in these brain angiotensin receptors may accelerate the progression of AD. Using post-mortem frontal cortex brain samples of age- and sex-matched cognitively normal individuals (n = 30) and AD patients (n = 30), we sought to dissect the b-RAS changes associated with AD and assess how these changes correlate with brain markers of oxidative stress, inflammation, and mitochondrial dysfunction as well as amyloid-β and paired helical filament tau pathologies. Our results show higher protein levels of the pro-inflammatory AT1R and phospho-ERK (pERK) in the brains of AD participants. Brain AT1R levels and pERK correlated with higher oxidative stress, lower cognitive performance, and higher tangle and amyloid-β scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology.

Immunohistochemical and Transcriptional Analysis of SARS-CoV-2 Entry Factors and Renin-Angiotensin-Aldosterone System Components in Lethal COVID-19

<b><i>Introduction:</i></b> Since angiotensin converting enzyme-2 (ACE2) was discovered as an essential entry factor of SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), there has been conflicting evidence regarding the role of renin-angiotensin-aldosterone system (RAAS) in COVID-19. This study elucidates pulmonary expression patterns SARS-CoV-2 entry factors (ACE2 and transmembrane protease serine subtype 2, TMPRSS2) and RAAS components in lethal COVID-19. <b><i>Methods:</i></b> Lung tissue from COVID-19 autopsies (<i>n</i> = 27) and controls (<i>n</i> = 23) underwent immunohistochemical staining for RAAS components (angiotensin receptors 1 and 2, ACE2 and Mas-receptor) and bradykinin receptors 1 and 2. Staining of individual cellular populations (alveolar pneumocytes [ALV], desquamated cells [DES] and endothelium [END]) was measured by a binary scale (positive/negative). SARS-CoV-2 was detected using immunohistochemistry against nucleocapsid protein, <i>in-situ</i> hybridization and quantitative reverse transcriptase polymerase chain reaction. Gene expression profiling for <i>ACE2, ACE</i> and <i>TMPRSS2</i> was performed. <b><i>Results:</i></b> Subtle differences were observed when comparing COVID-19 patients and controls not reaching statistical significance, such as a higher incidence of ACE2-positivity in END (52% vs. 39%) but lower positivity in ALVs (63% vs. 70%) and an overall downregulation of <i>ACE2</i> gene expression (0.25 vs. 0.55). However, COVID-19 patients with RAAS inhibitor (RAASi) intake had significantly shorter hospitalization times (5 vs. 12 days), higher viral loads (57,517 vs. 15,980/10⁶ RNase P-gene copies) and decreased <i>ACE/ACE2</i>-expression ratios (4.58 vs. 11.07) than patients without. <i>TMPRSS2</i> expression was significantly (1.76-fold) higher in COVID-19 patients than controls. <b><i>Conclusion:</i></b> Our study delineates the heterogeneous expression patterns of RAAS components in the lungs, which vary amongst cellular populations, and implies that COVID-19 patients with RAASi-intake present with a more rapid disease progression, although this requires further investigation.

Moderate Physical Exercise Activates ATR2 Receptors, Improving Inflammation and Oxidative Stress in the Duodenum of 2K1C Hypertensive Rats

Background: In addition to the cardiovascular and renal systems, the gastrointestinal tract also contains angiotensin ATR1a, ATR1b, and ATR2. We previously observed that the 2Kidney-1Clip hypertension model elicits physical exercise and gastrointestinal dysmotility, which is prevented by renin-angiotensin system blockers. Here, we investigate the effect of physical exercise on inflammation, stress biomarkers, and angiotensin II receptors in the duodenum of 2K1C rats.Methods: Arterial hypertension was induced by the 2K1C surgical model. The rats were allocated in Sham, 2K1C, or 2K1C+Exercise groups. One week after surgery, they were submitted to a physical exercise protocol (running 5x/week, 60min/day). Next, we assessed their intestinal contractility, cytokine levels (TNF-α, IL-1β, and IL-6), oxidative stress levels (MPO, GSH, MDA, and SOD), and the gene expression of angiotensin receptors (ATR1A, ATR1B, and ATR2).Results: In comparison with the Sham group, the 2K1C arterial hypertension decreased (p&lt;0.05) the intestinal contractility. In comparison with 2K1C, the 2K1C+Exercise group exhibited lower (p&lt;0.05) MPO activity (22.04±5.90 vs. 78.95±18.09 UMPO/mg tissue) and higher (p&lt;0.05) GSH concentrations in intestinal tissues (67.63±7.85 vs. 31.85±5.90mg NPSH/mg tissue). The 2K1C+Exercise group showed lower (p&lt;0.05) cytokine levels in the intestine than 2K1C rats. In comparison with the Sham group, the 2K1C+Exercise rats showed higher (p&lt;0.05) gene expression of ATR2 in the duodenum.Conclusion: 2K-1C hypertension elicits an oxidative stress and inflammation process in the duodenum. Physical exercise modulates the expression twice as much of ATR2 receptors, suggesting possible anti-inflammatory and antioxidant effects induced by exercise.

Shedding Light on the Pharmacological Interactions between μ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.

Aerobic Exercise Upregulates DNA Methylation of Agtr1a and Mas1 Genes to Improve Mesenteric Arterial Function in Spontaneously Hypertensive Rats

The imbalance between vasoconstrictive axis and vasodilative axis of the renin-angiotensin system (RAS) is involved in the pathogenesis of hypertension. Exercise modulates components of the RAS and influences vascular function. This study aimed to investigate the balance of RAS axes and the mechanism of DNA methylation of the Agtr1a (AT1aR) and Mas1 (MasR) genes in aerobic exercise-induced improvement of the function of mesenteric arteries (MAs) in hypertension. Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were subjected to exercise training or kept sedentary. Plasma RAS peptides, vascular function, and molecular properties were assessed. Aerobic exercise significantly decreased blood pressure in SHR. Plasma levels of RAS peptides increased in SHR, and the level of Ang II was much higher than Ang-(1–7), whereas exercise efficiently inhibited this inappropriate increase. In addition, Ang II-induced maximal contraction of MAs is largely through Type 1 angiotensin receptors (AT1R), while Mas receptor (MasR) inhibits this contribution. Exercise effectively suppressed hypertension-associated mRNA and protein expression upregulation of AT1R and MasR and increased MasR/AT1R ratio in SHR by triggering hypermethylation of Agtr1a and Mas1 genes, with increasing DNMT1 and DNMT3b protein expression and ratio of SAM/SAH. These findings suggest that aerobic exercise alleviates vascular tone by upregulating the methylation status of the Agtr1a and Mas1 genes and inhibiting the imbalanced increase in the vasoconstrictive and vasodilative axes during hypertension.

Megalin, Proton Pump Inhibitors and the Renin–Angiotensin System in Healthy and Pre-Eclamptic Placentas

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased in pre-eclampsia. The proton pump inhibitor (PPI) lowers sFlt-1, while angiotensin increases it. To investigate whether PPIs lower sFlt-1 by suppressing placental renin–angiotensin system (RAS) activity, we studied gene expression and protein abundance of RAS components, including megalin, a novel endocytic receptor for prorenin and renin, in placental tissue obtained from healthy pregnant women and women with early-onset pre-eclampsia. Renin, ACE, ACE2, and the angiotensin receptors were expressed at identical levels in healthy and pre-eclamptic placentas, while both the (pro)renin receptor and megalin were increased in the latter. Placental prorenin levels were upregulated in pre-eclamptic pregnancies. Angiotensinogen protein, but not mRNA, was detectable in placental tissue, implying that it originates from maternal blood. Ex vivo placental perfusion revealed a complete washout of angiotensinogen, while prorenin release remained constant. The PPI esomeprazole dose-dependently reduced megalin/(pro)renin receptor-mediated renin uptake in Brown Norway yolk sac epithelial cells and decreased sFlt-1 secretion from placental villous explants. Megalin inhibition blocked angiotensinogen uptake in epithelial cells. In conclusion, our data suggest that placental RAS activity depends on angiotensinogen taken up from the maternal systemic circulation. PPIs might interfere with placental (pro)renin-AGT uptake/transport, thereby reducing angiotensin formation as well as angiotensin-induced sFlt-1 synthesis.