The renin-angiotensin-system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. Indeed, dysregulation of the RAS may lead to the development of cardiovascular pathologies including kidney injury. Moreover, the blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS that the system is comprised of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE-Ang II-AT1R axis that promotes vasoconstriction, sodium retention, and other mechanisms to maintain blood pressure, as well as increased oxidative stress, fibrosis, cellular growth, and inflammation in pathological conditions. In contrast, the non-classical RAS composed of the ACE2-Ang-(1–7)-Mas receptor axis generally opposes the actions of a stimulated Ang II-AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and oxidative stress. Thus, a reduced tone of the Ang-(1–7) system may contribute to these pathologies as well. Moreover, the non-classical RAS components may contribute to the effects of therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury. The review considers recent studies on the ACE2-Ang-(1–7)-Mas receptor axis regarding the precursor for Ang-(1–7), the intracellular expression and sex differences of this system, as well as an emerging role of the Ang1-(1–7) pathway in fetal programing events and cardiovascular dysfunction.

The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT 1R) antagonists is an effective therapy to attenuate hypertension and diabetic renal injury, and to improve heart failure. Originally defined as a circulating system, multiple tissues express a complete RAS, and compelling evidence now favors an intracellular system involved in cell signaling and function. Within the kidney, intracellular expression of the three predominant ANG receptor subtypes is evident in the nuclear compartment. The ANG type 1 receptor (AT 1R) is coupled to the generation of reactive oxygen species (ROS) through the activation of phosphoinositol-3 kinase (PI3K) and PKC. In contrast, both ANG type 2 (AT 2R) and ANG-(1-7) (AT 7R) receptors stimulate nitric oxide (NO) formation, which may involve nuclear endothelial NO synthase (eNOS). Moreover, blockade of either ACE2-the enzyme that converts ANG II to ANG-(1-7)-or the AT 7 receptor exacerbates the ANG II-ROS response on renal nuclei. Finally, in a model of fetal programmed hypertension, the nuclear ROS response to ANG II is enhanced, while both AT 2 and AT7 stimulation of NO is attenuated, suggesting that an imbalance in the intracellular RAS may contribute to the development of programming events. We conclude that a functional intracellular or nuclear RAS may have important implications in the therapeutic approaches to cardiovascular disease. renin-angiotensin system; angiotensin converting enzyme; ACE2; neprilysin; kidney; nuclei; AT 1 ; AT 2 ; AT 7 , FROM THE EARLY STUDIES OF Tigerstedt and Bergman (101) that described renin activity in the kidney to the characterization of a pressor substance subsequently identified as ANG II by the laboratories of Braun-Menendez (6) (hypertensin) and Page (angiotonin) 50 years later (8), the characterization of the renin-angiotensin system (RAS) within the kidney and other tissues continues unabated to broaden our understanding of the functional aspects of this important hormonal system in blood pressure regulation and cardiovascular pathologies. Coupled with the discoveries of ANG I-converting enzyme (ACE) as the primary enzyme that forms ANG II in the circulation and tissue and the molecular identification of the ANG II type 1 receptor (AT 1 ) that confers the predominant actions of ANG II, the "classical" RAS was regarded as a sequential endocrine system to form ANG II for the maintenance of blood pressure through renal, vascular, and central mechanisms. There is, however, overwhelming evidence for a "nonclassical" RAS that results in the formation of novel peptide products with functional properties distinct from that of the ANG II-AT 1 receptor pathway (5,12,14,67,8...

Introduction Isolated nuclei of sheep proximal tubules express angiotensin receptors as well as angiotensinogen (AGT) and renin. The present study characterized the NRK-52E tubular epithelial cell line for the intracellular expression of renin-angiotensin system (RAS) components. Methods RAS components were visualized by immunofluorescent staining in intact cells and protein expression in isolate nuclei. Results An antibody to the Ang I sequence of AGT (AI-AGT) revealed only cytosolic staining, while an antibody to an internal epitope of AGT (Int-AGT) revealed primarily nuclear staining. Immunoblots of nuclear and cytosolic fractions confirmed the differential cell staining of AGT. Immunostaining for renin was present on nuclei of intact cells. Nuclear renin activity averaged 0.77 ± 0.05 nmol/mg protein/hr that was reduced by aliskiren (0.13 ± 0.01 nmol/mg/hr, n=3, p<0.01); trypsin activation increased activity 3-fold. Peptide staining localized Ang II and Ang-(1–7) to the nucleus and peptide content averaged 59 ± 2 and 57 ± 22 fmol/mg (n=4), respectively. Peptide metabolism in isolated nuclei revealed the processing of Ang I to Ang-(1–7) by thimet oligopeptidase. Conclusion We conclude that the NRK-52E cells express an intracellular RAS localized to the nucleus and may be an appropriate cell model to elucidate the functional relevance of this system.

Angiotensin-(1-7) (Ang-(1-7)/AT7-Mas receptor axis is an alternative pathway within the renin angiotensin system (RAS) that generally opposes the actions of Ang II/AT1 receptor pathway. Advanced glycated end product (AGEs) including glucose- and methylglyoxal-modified albumin (MGA) may contribute to the development and progression of diabetic nephropathy in part through activation of the Ang II/AT1 receptor system; however, the influence of AGE on the Ang-(1-7) arm of the RAS within the kidney is unclear. The present study assessed the impact of AGE on the Ang-(1-7) axis in NRK-52E renal epithelial cells. MGA exposure for 48 hours significantly reduced the intracellular levels of Ang-(1-7) approximately 50%; however, Ang I or Ang II expression was not altered. The reduced cellular content of Ang-(1-7) was associated with increased metabolism of the peptide to the inactive metabolite Ang-(1-4) [MGA: 175 ± 9 vs. Control: 115 ± 11 fmol/min/mg protein, p<0.05, n=3] but no change in the processing of Ang I to Ang-(1-7). Treatment with Ang-(1-7) reversed MGA-induced cellular hypertrophy and myofibroblast transition evidenced by reduced immunostaining and protein expression of α-smooth muscle actin (α-SMA) [0.4±0.1 vs. 1.0±0.1, respectively, n=3, p<0.05]. Ang-(1-7) abolished AGE-induced activation of the MAP kinase ERK1/2 to a similar extent as the TGF-β receptor kinase inhibitor SB58059; however, Ang-(1-7) did not attenuate the MGA-stimulated release of TGF-β. The AT7-Mas receptor antagonist D-Ala7-Ang-(1-7) abolished the inhibitory actions of Ang-(1-7). In contrast, AT1 receptor antagonist losartan did not attenuate the MGA-induced effects. We conclude that Ang-(1-7) may provide an additional therapeutic approach to the conventional RAS blockade regimen to attenuate AGE-dependent renal injury.

The kidney is a key target organ for bioactive components of the renin-angiotensin system (RAS); however, various renal cells such as the tubular epithelium contain an intrinsic RAS. The renal RAS can be functionally divided into ANG II-AT1 receptor and ANG-(1-7)-AT7/Mas receptor arms that functionally oppose one another. The current review considers both extracellular and intracellular pathways that potentially govern the formation and metabolism of angiotensin peptides within the renal proximal tubules.

The purpose of the current study was to examine the association of serum copper and lipid concentrations with changes in cognitive function in elderly Jordanian individuals. The study population consisted of two groups: 52 dementia patients and 50 control subjects. All individuals were screened using the Mini-Mental State Examination and Clock Drawing Test. Serum copper and lipid profile were also assessed. Results were statistically evaluated at p < 0.05 level of significance. The dementia group had 10.1% higher copper level than control subjects that was not statistically significant. No significant differences could be found between the two groups in lipid profile levels. There was no significant correlation between serum copper, lipid profile, and cognitive decline in elderly Jordanians. Demographic variables indicated that educational level less than 12 years and illiterate demonstrated a 3.29 fold (p = 0.026) and 6.29 fold (p = 0.002) increase in risk of developing dementia, respectively. Coffee intake demonstrated a protective effect against cognitive decline with 6.25 fold lower risk with increased coffee intake.

Objectives To assess serum 25-hydroxycholecalciferol (25-OH vitamin D) levels in Jordanian children with bronchial asthma, and to examine correlations between 25-OH vitamin D levels and asthma severity and control. Methods A cross-sectional study was conducted at the Paediatric Chest Clinic, Al-Karak Governmental Hospital, Southern Jordan, between May 2015 and February 2016. Serum 25-hydroxyvitamin D level was determined in children aged 1–14 years diagnosed with bronchial asthma (6–14 years) or recurrent wheezing episodes (<6 years). Asthma severity was determined based on the Global Initiative for Asthma assessment, the Asthma Control Test, and the Childhood Asthma Control Test. Demographic and clinical characteristics were compared between patients with low and normal 25-OH vitamin D levels, and correlations between asthma severity and 25-OH vitamin D level were assessed. Results Out of 98 included children, 25-OH vitamin D levels were deficient and insufficient in 41 (41.8%) and 34 (34.7%) children, respectively. Only 23 (23.5%) had sufficient 25-OH vitamin D levels. A significant correlation was found between severity of asthma symptoms and 25-OH vitamin D deficiency. Conclusion 25-OH vitamin D deficiency is highly prevalent in Jordanian children with bronchial asthma and correlates significantly with asthma severity.

BackgroundSensitization to inhaled allergens in children with bronchial asthma significantly affects asthma pathogenesis, severity and persistence into late childhood and adulthood. The present study determined the prevalence of sensitization to inhaled allergens in children with bronchial asthma and wheezing episodes in order to investigate the effect of positive sensitization on the severity and control of asthma symptoms and to screen for other associated allergic conditions.MethodsA cross-sectional study was conducted, including children between 6 months and 14 years of age attending the chest clinic of Al-Karak, south of Jordan, between November 2013 and February 2016. Skin prick tests (SPTs) using 11 standardized allergen extracts were conducted in 277 children. The severity of asthma was determined based on the Global Initiative for Asthma (GINA) assessment and the Childhood Asthma Control Test (C-ACT) in addition to the history of use of systemic steroids and hospital admissions within the past 12 months.ResultsSixty-seven percent of children with bronchial asthma reported sensitization to one or more of the inhaled allergens. The most common allergens were olive pollens (18%), cat fur (13.5%), and Dermatophagoides pteronyssinus (11.9%). There was a significant increase in allergen sensitization with age (p < 0.001). The most common concomitant allergic condition among children was allergic rhinitis (71.5%); however, allergic conjunctivitis was the only allergic condition that correlated with the skin test reactivity (p = 0.01). A family history of bronchial asthma was confirmed in 40.4% of children. Children with positive SPTs had lower ACT scores and reported more frequent use of systemic steroids and admissions to hospital within the past 12 months; however, this effect was not statistically significant (p > 0.05).ConclusionsSensitization to inhaled allergens is highly prevalent in children with asthma and wheezing episodes in southern Jordan and may be correlated with the severity of the disease. Therefore, appropriate measures to recognize and avoid these allergens are highly recommended. Most children in our study suffered from concomitant allergic rhinitis, indicating that an appropriate diagnosis and treatment of allergic rhinitis could significantly improve asthma control and thus the quality of life of these children.Trial registrationThis study is not a clinical trial.