Alterations In Renin-angiotensin System Research Articles

ACE2/ACE imbalance mediates bisphenol A-induced lung injury in Wistar rats: Results from captopril versus losartan histo-biochemical study

Bisphenol-A (BPA) is a synthetic chemical compound broadly used in the plastic and epoxy resin industries with a considerable potential for food contamination. Literary reports have suggested that the altered renin-angiotensin system (RAS) is a mechanism for lung injury and inflammation caused by variable agents. The current study sought to investigate the contribution of RAS to BPA-induced lung damage. Moreover, the study assessed whether angiotensin II and/or bradykinin pathways were involved. For this aim, the angiotensin-converting enzyme (ACE) inhibitor captopril (Cap), either alone or combined with bradykinin receptor antagonist icatibant (Icat), was attempted versus the angiotensin receptor blocker losartan (Los). An eight-week study was conducted on forty Wistar male albino rats randomly divided into five equal groups: control, BPA, BPA/Cap, BPA/Los, and BPA/Cap/Icat groups. Captopril (100 mg/mL) and losartan (200 mg/mL) were given orally in drinking water, but icatibant (Icat) was injected subcutaneously (250 μg/kg) during the last two weeks of captopril treatment. Biochemical analysis of bronchoalveolar lavage fluid (BALF) and lung tissues, polymerase chain reaction (PCR) assay for ACE, ACE2, and caspase-3 genes expression, and histological and immunohistochemical studies were carried out to evaluate BPA-mediated pulmonary inflammation/apoptosis. BPA impaired the histological structure of the lungs, increased ACE, ACE2, and caspase-3 expressions at both gene/protein levels, and increased BALF inflammatory cytokines and lung oxidative markers. Inhibiting the ACE activity by captopril maintained the histological lung injury score, restored inflammation and the ACE2/ACE balance, and decreased apoptosis. Further improvement was obtained by the angiotensin II receptor (ATR1) blocker losartan. Icatibant (bradykinin B2 receptor blocker) didn't counteract the observed captopril effects. It was strongly suggested that RAS contributed to BPA-induced lung damage via alteration of ACE2 and ACE expression mediating angiotensin II generation rather than bradykinin.

Alterations in Renin-Angiotensin System (RAS) Peptide Levels in Patients with HIV.

Chronic HIV infection has long been associated with an increased risk for cardiovascular diseases. The metabolites of the renin−angiotensin system (RAS) such as angiotensin II (AngII) play an important role in regulating blood pressure and fluid dynamics. Cross-sectional analysis of HIV-positive individuals (n = 71, age > 40 years, stable ART > 3 months with HIV viral load < 50 copies/mL) were compared to a similar HIV seronegative group (n = 72). High-resolution B-mode ultrasound images of the right carotid bifurcation (RBIF) and right common carotid artery (RCCA) were conducted to measure the extent of carotid atherosclerotic vascular disease. Plasma RAS peptide levels were quantified using a liquid chromatography-mass spectrometry-based metabolomics assay. RAS peptide concentrations were compared between persons with HIV and persons without HIV, correlating their association with clinical and cardiac measures. Median precursor peptides (Ang(1-12) and AngI) were significantly higher in the HIV-positive group compared to the HIV-negative. Analyses of the patient subgroup not on antihypertensive medication revealed circulating levels of AngII to be four-fold higher in the HIV-positive subgroup. AngII and TNF-alpha levels were found to have a positive association with RCCA, and AngI/Ang(1-12) ratio and TNF-alpha levels were found to have a positive association with RBIF. In both predictive models, AngIII had a negative association with either RCCA or RBIF, which may be attributed to its ability to bind onto AT2R and thus oppose pro-inflammatory events. These results reveal systemic alterations in RAS as a result of chronic HIV infection, which may lead to the activation of inflammatory pathways associated with carotid thickening. RAS peptide levels and cytokine markers were associated with RCCA and RBIF measurements.

CARDIOVASCULAR RISK MARKERS IN PATIENTS WITH STRUCTURAL AND NUMERIC ABERRATIONS OF X CHROMOSOME

To assess the relationship between RAS, karyotype and cardiovascular risk factors in patients with X chromosome abnormalities.Observational, prospective study with 7 years of evolution. Inclusion Criteria: Presence of aberrations that affect the number or morphology of the X chromosome in karyotype study. Exclusion Criteria: Those who did not give their informed consent to participate in the study. The detection of Y chromosome sequences was performed. The cardiovascular risk factors present were analyzed. Furthermore, exploration of carotid intimal thickness is by ultrasound was performed. The degree of dynamic endothelial dysfunction in the brachial artery (BMD) was also determined. ACE2 and Angiotensin II genes expression were indirectly evaluated in peripheral blood.The monosomy of the X chromosome was the most frequent. There are 57.4% had overweight or obese, 23% had diabetes, 40% had a new diagnosis of hypertension, and 51% had dyslipidemia. In no case, in the patients evaluated with Turner syndrome, was the presence of the Y chromosome sequence found. One patient was found with a short-arm duplication that includes the SHOX gene, evaluated by MLPA. 89% of the patients presented endothelial dysfunction parameters, and 22% presented carotid plaques in the ultrasound study. In multivariate analysis, patients were separated into tertiles, according to the amount of X chromosomal material in the cytogenetic formula to analyze vascular findings. (Table 1).Central obesity present in childhood and adolescence could contribute to the early diagnosis of the metabolic syndrome so characteristic in these patients. The presence of hypertension could have relationship with renin-angiotensin system alterations. Women with monosomy are the ones who would most suffer an early lack of the protective effect of ACE2 with its vasodilator, antiproliferative and antifibrotic properties, among others. The vascular alterations were an independent factor of the variables studied.

Fluorescence detection of the human angiotensinogen protein by the G-quadruplex aptamer.

Noncanonical G-quadruplex nucleic acid structures can be used as probes in biosensors for the detection of metal ions, proteins and nucleic acids. Angiotensinogen (AGT) is a glycosylated globulin found in serum, which can regulate blood pressure and body fluid homeostasis. AGT is an important part of the renin-angiotensin system (RAS) and can be potentially used as a biomarker of diseases with RAS alterations. G-quadruplex based biosensors can detect targets with high accuracy and speed and low cost. Employing the magnetic bead enrichment method we constructed a reliable and efficient fluorescent biosensor platform for G-quadruplex based detection of the human AGT protein. The primary antibody in our biosensor is recognized by fluorescently labeled secondary antibodies, which leads to the detection of AGT captured by the G-quadruplex aptamer coupled magnetic beads. This G-quadruplex based fluorescent biosensor designed with a detection limit of 5 × 10-5 mg mL-1 was used for the successful detection of AGT at the cellular level. Our G-quadruplex based fluorescent biosensor will contribute to the more reliable and efficient detection of AGT.

Inhalation exposure to silver nanoparticles induces hepatic inflammation and oxidative stress, associated with altered renin-angiotensin system signaling, in Wistar rats.

Silver nanoparticles (AgNPs) have become increasingly popular in the biomedical field over the last few decades due to its proven antibacterial property. Previous scientific studies have reported that one of the major organs responsible for detoxification of AgNPs is the liver. The liver is also the primary organ responsible for secretion of angiotensinogen (AGT), a key signaling molecule involved in the renin-angiotensin system (RAS), which plays an important role in maintaining cardiac output and vascular pressure. The aim of this study was to assess any potential changes in the RAS-associated gene signaling, inflammatory response, and hepatocellular toxicity resulting from AgNP exposure. To do this, 6-week-old, male Wistar rats were exposed to a subacute inhalation exposure of AgNP (200 ppb/days over 4h/days exposure, for 5d) and their livers were analyzed for alterations in RAS components, inflammation, and oxidative stress. Real time qPCR analysis showed that AgNP-exposure resulted in a significant increase in hepatic AGT, angiotensin converting enzyme (ACE)-1, and ACE-2 mRNA expression. Expression of inflammatory markers interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were also upregulated with AgNP-exposure, compared to controls. Furthermore AgNP-exposure mediated a significant increase in hepatic expression of catalase, and superoxide dismutase, and oxidative stress, as assessed via 8-Oxo-2'-deoxyguanosine staining. Increased oxidative stress was associated with increased monocyte/macrophage-2 staining in the liver of AgNP-exposed rats. Such findings indicate that subacute inhalation exposure to AgNPs mediate increased hepatic RAS signaling, associated with inflammation, macrophage infiltration, and oxidative stress.

The Type of Fat in the Diet Influences Regulatory Aminopeptidases of the Renin-Angiotensin System and Stress in the Hypothalamic-Pituitary-Adrenal Axis in Adult Wistar Rats.

(1) Background: Prolonged feeding with a high-fat diet (HFD) acts as a stressor by activating the functions of the hypothalamic-pituitary-adrenal gland (HPA) stress axis, accompanied of hypertension by inducing the renin-angiotensin-aldosterone system. Angiotensinases enzymes are regulatory aminopeptidases of angiotensin metabolism, which together with the dipeptidyl peptidase IV (DPP-IV), pyroglutamyl- and tyrosyl-aminopeptidase (pGluAP, TyrAP), participate in cognitive, stress, metabolic and cardiovascular functions. These functions appear to be modulated by the type of fat used in the diet. (2) Methods: To analyze a possible coordinated response of aminopeptidases, their activities were simultaneously determined in the hypothalamus, adenohypophysis and adrenal gland of adult male rats fed diets enriched with monounsaturated (standard diet (S diet) supplemented with 20% virgin olive oil; VOO diet) or saturated fatty acids (diet S supplemented with 20% butter and 0.1% cholesterol; Bch diet). Aminopeptidase activities were measured by fluorimetry using 2-Naphthylamine as substrates. (3) Results: the hypothalamus did not show differences in any of the experimental diets. In the pituitary, the Bch diet stimulated the renin-angiotensin system (RAS) by increasing certain angiotensinase activities (alanyl-, arginyl- and cystinyl-aminopeptidase) with respect to the S and VOO diets. DPP-IV activity was increased with the Bch diet, and TyrAP activity decrease with the VOO diet, having both a crucial role on stress and eating behavior. In the adrenal gland, both HFDs showed an increase in angiotensinase aspartyl-aminopeptidase. The interrelation of angiotensinases activities in the tissues were depending on the type of diet. In addition, correlations were shown between angiotensinases and aminopeptidases that regulate stress and eating behavior. (4) Conclusions: Taken together, these results support that the source of fat in the diet affects several peptidases activities in the HPA axis, which could be related to alterations in RAS, stress and feeding behavior.

Gut microbiota and renin-angiotensin system: a complex interplay at local and systemic levels.

Gut microbiota is a potent biological modulator of many physiological and pathological states. The renin-angiotensin system (RAS), including the local gastrointestinal RAS (GI RAS), emerges as a potential mediator of microbiota-related effects. The RAS is involved in cardiovascular system homeostasis, water-electrolyte balance, intestinal absorption, glycemic control, inflammation, carcinogenesis, and aging-related processes. Ample evidence suggests a bidirectional interaction between the microbiome and RAS. On the one hand, gut bacteria and their metabolites may modulate GI and systemic RAS. On the other hand, changes in the intestinal habitat caused by alterations in RAS may shape microbiota metabolic activity and composition. Notably, the pharmacodynamic effects of the RAS-targeted therapies may be in part mediated by the intestinal RAS and changes in the microbiome. This review summarizes studies on gut microbiota and RAS physiology. Expanding the research on this topic may lay the foundation for new therapeutic paradigms in gastrointestinal diseases and multiple systemic disorders.

Renin-angiotensin system in intestinal inflammation-Angiotensin inhibitors to treat inflammatory bowel diseases?

Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract, which manifest in recurring gastrointestinal inflammation. The current treatment options of IBD are not curative and are lacking in aspects like prevention of fibrosis. New treatment options are needed to fulfil the unmet needs and provide alternatives to drugs with resistances and side effects. Drugs targeting the renin-angiotensin system (RAS), besides being antihypertensive, also possess anti-inflammatory and antifibrotic properties and could offer an inexpensive alternative to control inflammation and fibrosis in the gut. RAS inhibitors have been effective in preventing and alleviating colitis in preclinical studies, but available human data are still sparse. This review outlines the pathophysiological functions of RAS in the gut and summarizes preclinical studies utilizing pharmacological RAS inhibitors in the treatment of experimental colitis. We discuss the alterations in intestinal RAS and the available evidence of the benefits of RAS inhibitors for IBD patients. Retrospective studies comparing IBD patients using ACE inhibitors or angiotensin II receptor blockers have provided optimistic results regarding a milder disease course and fewer hospitalizations and corticosteroid use in patients using RAS inhibitors. Prospective studies are needed to evaluate the effectiveness of these promising medications in the treatment of IBD.

SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to increase the risk of adverse pregnancy outcomes, such as pre-eclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear.MethodsWe investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta, which controls blood pressure, we treated human trophoblasts with recombinant spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing spike protein (VSV-S).FindingsViral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing angiotensin-converting enzyme 2 (ACE2) and demonstrate that infected placentas had significantly reduced ACE2. In response to both spike protein and VSV-S, cellular ACE2 decreased although angiotensin II receptor type 1 (AT1R) increased with concomitant increase in soluble fms-like tyrosine kinase-1 (sFlt1). Viral infection decreased pro-angiogenic factors, AT2R, and placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and angiotensin II type 1-receptor autoantibodies prior to delivery, both signatory markers of pre-eclampsia.ConclusionsSARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes, such as pre-eclampsia in pregnant women.FundingNIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement).

Angiotensin-converting enzyme 2 influences pancreatic and renal function in diabetic mice

AbstractType 1 diabetes is a T-cell mediated autoimmune disease characterized by pancreatic beta cells destruction. Angiotensin-converting enzyme 2 (ACE2), a component of renin–angiotensin system (RAS) has been identified in pancreas from type 2 diabetic mice and its overexpression prevents beta cell dysfunction. We studied the effect of ACE2 deletion on pancreatic and renal function in the nonobese diabetic mice, a model that mimics type 1 diabetes. ACE2-deficient NOD mice and the respective controls were generated. Pancreas function and immunohistochemistry studies were performed. Renal function and RAS gene expression were also analyzed. Renal proximal tubular cells were obtained from these animals to dissect the effect of ACE2 deficiency in these cells. In NOD mice, ACE2 deletion significantly worsened glucose homeostasis, decreased islet insulin content, increased beta cell oxidative stress, and RIPK1-positive islets as compared with control mice. Angiotensin-converting enzyme and angiotensin II type 1 receptor (AT1R) were also increased in ACE2-deficient mice. In kidneys of 30-day diabetic mice, ACE2 deletion decreased podocyte number within the glomeruli, and altered renal RAS gene expression in tubules. ACE2 deletion influenced the expression of fibrosis-related genes in isolated primary renal proximal tubular cells before diabetes onset in NOD mice. Our findings suggest that ACE2 deletion may have a deleterious impact on beta cell and renal function, by promoting oxidative stress and increasing necroptosis mediators. In addition, this effect is accompanied by RAS alterations in both pancreas and renal proximal tubular cells, indicating that ACE2 may exert a renopancreatic protective effect on type 1 diabetes, which is activated before diabetes starts.This study examined the contribution of ACE2 in diabetes onset and the role of ACE2 in the progression of diabetic nephropathy in NOD mouse. ACE2 loss leads to an impaired glucose and insulin homeostasis, RAS activation, increase in oxidative stress, and RIPK1 within the pancreas. In the kidney, ACE2 deletion induced podocyte loss, RAS modulation, and renal fibrosis activation in an early phase of diabetes.

Effect of hyperglycemia and rosiglitazone on renal and urinary neprilysin in db/db diabetic mice.

Alteration in renin‐angiotensin system (RAS) has been implicated in the pathophysiology of diabetic kidney disease (DKD). The deleterious actions of angiotensin II (Ang II) could be antagonized by the formation of Ang‐(1–7), generated by the actions of angiotensin‐converting enzyme 2 (ACE2) and neprilysin (NEP). NEP degrades several peptides, including natriuretic peptides, bradykinin, amyloid beta, and Ang I. Although combination of Ang II receptor and NEP inhibitor treatment benefits patients with heart failure, the role of NEP in renal pathophysiology is a matter of active research. NEP pathway is a potent enzyme in Ang I to Ang‐(1–7) conversion in the kidney of ACE2‐deficient mice, suggesting a renoprotective role of NEP. The aim of the study is to test the hypothesis that chronic hyperglycemia downregulates renal NEP protein expression and activity in db/db diabetic mice and treatment with rosiglitazone normalizes hyperglycemia, renal NEP expression, and attenuates albuminuria. Mice received rosiglitazone (20 mg kg−1 day−1) for 10 weeks. Western blot analysis, immunohistochemistry, and enzyme activity revealed a significant decrease in renal and urinary NEP expression and activity in 16‐wk db/db mice compared with lean control (p < .0001). Rosiglitazone also attenuated albuminuria and increased renal and urinary NEP expressions (p < .0001). In conclusion, data support the hypothesis that diabetes decreases intrarenal NEP, which could have a pivotal role in the pathogenesis of DKD. Urinary NEP may be used as an index of intrarenal NEP status. The renoprotective effects of rosiglitazone could be mediated by upregulation of renal NEP expression and activity in db/db diabetic mice.

Hypertension and Electrolyte Disorders in Patients with COVID-19.

The worldwide coronavirus disease 2019 (COVID-19) pandemic is still in progress, but much remains unknown about the disease. In this article, we review the association of hypertension or the renin-angiotensin system (RAS) with COVID-19 and the correlation between electrolyte disorders and disease severity. Underlying hypertension is likely to be associated with severe or critical COVID-19, but the relationship is not clear owing to confounding factors. Angiotensin-converting enzyme 2 (ACE2) plays an important role in the non-classical RAS pathway and binds to a receptor binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The RAS blockade is known to increase ACE2 levels, but controversy remains regarding the effect of RAS blockade therapy in the course of COVID-19. Some reports have indicated a protective effect of RAS blockade on COVID-19, whereas others have reported an association of RAS blockade therapy with the occurrence of severe complications such as acute kidney injury and admission to the intensive care unit. Electrolyte disorders are not uncommon in patients with COVID-19, and severe COVID-19 has frequently shown hypokalemia, hyponatremia, and hypocalcemia. Electrolyte imbalances are caused by alteration of RAS, gastrointestinal loss, effects of proinflammatory cytokines, and renal tubular dysfunction by the invasion of SARS-CoV-2.

Intrarenal Renin-Angiotensin System Involvement in the Pathogenesis of Chronic Progressive Nephropathy-Bridging the Informational Gap Between Disciplines.

Chronic progressive nephropathy (CPN) is the most commonly encountered spontaneous background finding in laboratory rodents. Various theories on its pathogenesis have been proposed, but there is a paucity of data regarding specific mechanisms or physiologic pathways involved in early CPN development. The current CPN mechanism of action for tumorigenesis is largely based on its associated increase in tubular cell proliferation without regard to preceding subcellular degenerative changes. Combing through the published literature from multiple biology disciplines provided insight into the preceding cellular events. Mechanistic pathways involved in the progressive age-related decline in rodent kidney function and several key inflexion points have been identified. These critical pathway factors were then connected using data from renal models from multiple rodent strains, other species, and mechanistic work in humans to form a cohesive picture of pathways and protein interactions. Abundant data linked similar renal pathologies to local events involving hypoxia (hypoxia-inducible factor 1α), altered intrarenal renin-angiotensin system (RAS), oxidative stress (nitric oxide), and pro-inflammatory pathways (transforming growth factor β), with positive feedback loops and downstream effectors amplifying the injury and promoting scarring. Intrarenal RAS alterations seem to be central to all these events and may be critical to CPN development and progression.

Simultaneous inhibition of neprilysin and activation of ACE2 prevented diabetic cardiomyopathy.

Neprilysin inhibitors (NEPi) are assisting the renin-angiotensin system (RAS) inhibitors in halting diabetic cardiomyopathy (DCM). Away from conventional tactic, a recent report revealed the renoprotective potential of NEPi and angiotensin-converting enzyme (ACE2) activator combination therapy against diabetic nephropathy. However, this combination so far not evaluated against DCM, thus the present investigation aiming the same. Streptozotocin-induced (55 mg/kg, ip) type 1 diabetic (T1D) male Wistar rats were treated with either monotherapy of thiorphan (0.1 mg/kg/day, po) or diminazene aceturate (5 mg/kg/day, po), or their combination therapy, for four weeks. After hemodynamic measurements, all the rats' heart and plasma were collected for biochemistry, ELISA, histopathology, and immunoblotting. Metabolic perturbations and failing cardiac functions associated with diabetes were markedly attenuated by combination therapy. Besides, unfavourable alterations in RAS and natriuretic peptides system (NPS) were corrected by combination therapy. Interestingly, combination therapy significantly increased plasma and heart cGMP levels compared to T1D and monotherapy receiving rats. Moreover, rats receiving combination therapy exhibited significant inhibition of activated NF-κB, TGF-β and apoptotic signalling, and a notable reduction in cardiac fibrosis when compared to T1D rats. Expressions of posttranslational histone modifications markers; H3K4Me2 and its methyltransferases (SET7/9 and RBBP5) were significantly enhanced in T1D hearts, which were significantly reduced by combination therapy. The NEPi and ACE2 activator combination therapy effectively prevented DCM by normalising RAS and NPS activities, increasing cGMP, inhibiting inflammatory, pro-fibrotic and apoptotic signalling, and reversing H3K4Me2 and its methyl transferases expressions.

Metformin attenuates cardiovascular and renal injury in uninephrectomized rats on DOCA-salt: Involvement of AMPK and miRNAs in cardioprotection

Hypertension is associated with major cardiovascular (CV) and renal complications. The molecular intricacy by which hypertension leads to end organ damage is not known. To address this, we aimed to determine the effect of deoxycorticosterone acetate (DOCA) –salt (sodium chloride)-induced hypertension on the alterations in renin-angiotensin system, leading to CV and renal dysfunction in uninephrectomized male Sprague Dawley rats. MicroRNAs involved in this were also not yet explored. Metformin was used to delineate the role of AMPK in mitigating the hypertension-induced CV and renal dysfunction. Administering DOCA and offering saline to uninephrectomized rats, induced hypertension and associated abnormalities of diastolic dysfunction, CV and renal hypertrophy and fibrosis via activating local renin angiotensin system. Western blotting and RT-qPCR analysis of diseased heart revealed decreased SERCA2, p-AMPK, miR-146a, miR-99b and increased miR-155 and metformin administered, at dose of 300 mg/kg/day, for a period of 8 weeks prevented CV and renal damage. To our knowledge, we are the first to show that involvement of epigenetic alterations at microRNA level might be responsible for hypertension-induced cardiac dysfunction and metformin reverses these alterations.

Dysregulation of microRNAs and renin-angiotensin system in high salt diet-induced cardiac dysfunction in uninephrectomized rats.

Uninephrectomy is not associated with major adverse events in cardiovascular and renal functions of live kidney donors. The effect of high salt diet on the quality of life of live kidney donors is largely unknown. Hence in this study, we aimed to determine the effect of high salt diet on the alterations of renin-angiotensin system and microRNAs leading to CV and renal dysfunction in uninephrectomized rats. In order to mimic clinical scenario, uninephrectomized male Sprague Dawley rats were fed initially with normal pellet diet for 12 weeks and then for 20 weeks with high salt (10% w/w NaCl) diet. At the end of the study, biochemical, functional, histological and molecular parameters were measured. High salt diet feeding resulted in renal dysfunction & fibrosis, decreased baroreflex sensitivity, increased in vivo cardiovascular reactivity to angiotensin II owing to upregulation of angiotensin II type 1 receptors and L-type calcium channels leading to cardiovascular dysfunction in uninephrectomized rats (UNX+HSD) worse than that of normal (binephric) rats fed with high salt diet (HSD). Protein expression of functional and hypertrophic protein markers revealed decreased SERCA, p-AMPK and increased p-AKT. Interestingly, levels of miR-25, miR-451 and miR-155 increased and miR-99 decreased in heart of uninephrectomized rats fed with high salt. However, circulating miR-25 and miR-451 levels decreased and miR-99b increased in these animals. Our study points out that since tissue and circulating levels of miRNAs are not similar, caution must be exercised during the usage of miRs as diagnostic or prognostic biomarkers. To our knowledge, we are the first to show that epigenetic alterations result in cardiac dysfunction in uninephrectomized rats fed with high salt diet.

Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease.

The pathways implicated in diabetic kidney disease (DKD) are largely derived from animal models. To examine if alterations in renin-angiotensin system (RAS) in humans are concordant with those in rodent models, we measured concentration of angiotensinogen (AOG), cathepsin D (CTSD), angiotensin-converting enzyme (ACE), and ACE2 and enzymatic activities of ACE, ACE2, and aminopeptidase-A in FVB mice 13-20 wk after treatment with streptozotocin (n = 9) or vehicle (n = 15) and people with long-standing type 1 diabetes, with (n = 37) or without (n = 81) DKD. In streptozotocin-treated mice, urine AOG and CTSD were 10.4- and 3.0-fold higher than in controls, respectively (P < 0.001). Enzymatic activities of ACE, ACE2, and APA were 6.2-, 3.2-, and 18.8-fold higher, respectively, in diabetic animals (P < 0.001). Angiotensin II was 2.4-fold higher in diabetic animals (P = 0.017). Compared with people without DKD, those with DKD had higher urine AOG (170 vs. 15 μg/g) and CTSD (147 vs. 31 μg/g). In people with DKD, urine ACE concentration was 1.8-fold higher (1.4 vs. 0.8 μg/g in those without DKD), while its enzymatic activity was 0.6-fold lower (1.0 vs. 1.6 × 109 RFU/g in those without DKD). Lower ACE activity, but not ACE protein concentration, was associated with ACE inhibitor (ACEI) treatment. After adjustment for clinical covariates, AOG, CTSD, ACE concentration, and ACE activity remained associated with DKD. In conclusion, in mice with streptozotocin-induced diabetes and in humans with DKD, urine concentrations and enzymatic activities of several RAS components are concordantly increased, consistent with enhanced RAS activity and greater angiotensin II formation. ACEI use was associated with a specific reduction in urine ACE activity, not ACE protein concentration, suggesting that it may be a marker of exposure to this widely-used therapy.

Perinatal Taurine Supplementation Alters Renal Function via Renin-Angiotensin System Overactivity in Adult Female Rats.

This study tests the hypothesis that perinatal taurine supplementation followed by a high sugar diet since weaning impairs renal function via renin-angiotensin system (RAS) overactivity in adult female rats. Female Sprague-Dawley rats were fed normal rat chow and given water alone or water containing 3% taurine from conception until weaning. After weaning, the female rats received normal rat chow and water with (CG, TSG) or without (CW, TSW) 5% glucose throughout the experiment. At 7-8 weeks of age, renal function at rest and after an acute saline load was tested in conscious female rats after a week of captopril treatment. Body, heart, and kidney weights were not significantly different among the eight groups. Mean arterial pressures and heart rates were also not different among the groups. While effective renal blood flow did not significantly differ among the eight groups, TSG displayed higher renal vascular resistance compared to CW, CG, and TSW groups. Glomerular filtration rate, filtration fraction, and water and sodium excretion did not significantly differ among the groups. Compared to CW, the saline load significantly depressed fractional water excretion in CG and TSW and fractional sodium excretion in CG, TSW, and TSG groups. Captopril treatment abolished these differences but significantly decreased potassium excretion in CG, TSW, and TSG compared to CW and abolished the increased fractional potassium excretion in TSG compared to CG and TSW groups. These data strongly suggest that in adult female rats, perinatal taurine supplementation, particularly followed by high sugar intake, alters renal function via altered RAS activity.

Local and systemic renin-angiotensin system participates in cardiopulmonary-renal interactions in monocrotaline-induced pulmonary hypertension in the rat.

Renin-angiotensin system (RAS) is one of the pathophysiological mechanisms in heart failure. Recently, involvement of the kidney in the disease progression has been proposed in patients with pulmonary arterial hypertension (PAH). We hypothesized that local and systemic RAS could be the central regulators of cardiopulmonary-renal interactions in experimental monocrotaline-induced pulmonary hypertension (PH) in rats. Male 12-week-old Wistar rats were injected subcutaneously with monocrotaline (60mg/kg). The experiment was terminated 4weeks after monocrotaline administration. Using RT-PCR, we measured the expression of RAS-related genes in right and left ventricles, lungs and kidneys, together with indicators of renal dysfunction and damage. We observed a significantly elevated expression of angiotensin-converting enzyme (ACE) in both left and right ventricles and kidneys (P<0.05), but a significantly decreased ACE in the lungs (P<0.05). Kidneys showed a significant 2.5-fold increase in renin mRNA (P<0.05) along with erythropoietin, TGFβ1, COX-2, NOS-1 and nephrin. Expression of erythropoietin correlated inversely with hemoglobin oxygen saturation and positively with renin expression. In conclusion, monocrotaline-induced PH exhibited similar alterations of ACE expression in the left and right ventricles, and in the kidney, in contrast to the lungs. Increased renal renin was likely a consequence of renal hypoxia/hypoperfusion, as was increased renal erythropoietin expression. Alterations in RAS in the monocrotaline model are probably a result of hypoxic state, and while they could serve as a compensatory mechanism at a late stage of the disease, they could be viewed also as an indicator of multiorgan failure in PAH.

MP67-19 ALISKIREN PROVIDES INCOMPLETE PROTECTION OF THE KIDNEY IN UNILATERAL URETERIC OBSTRUCTION IN THE RAT

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology II1 Apr 2016MP67-19 ALISKIREN PROVIDES INCOMPLETE PROTECTION OF THE KIDNEY IN UNILATERAL URETERIC OBSTRUCTION IN THE RAT Fayez Hammad and Loay Lubbad Fayez HammadFayez Hammad More articles by this author and Loay LubbadLoay Lubbad More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1335AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Ureteric obstruction (UO) is a common urological condition caused by several conditions such as urolithiasis and might lead to renal impairment. UO induces alterations in renin angiotensin system (RAS) which plays an important role in obstruction-induced renal dysfunction. Renin catalyzes the first and rate limiting step of RAS. However, until recently, direct renin inhibitors were not used effectively in clinical practice due to toxicity, poor bioavailability and limited efficacy. Aliskiren is the first commercially available FDA-approved oral direct renin inhibitor. Very few studies showed that aliskiren ameliorates some of the UO-induced markers of acute renal injury. However, these protective effects do not necessarily imply an improvement in the UO-induced alterations in some of the clinically more relevant parameters such as the glomerular filtration rate (GFR), renal blood flow (RBF) and tubular functions. Indeed, the effect of aliskiren on these parameters in the post-obstruction period has not been studied yet. Thus, the aim of this study was to investigate the effect of aliskiren on the alterations in renal dysfunction following reversible unilateral UO in the rat. METHODS Male Wistar rats underwent reversible left UO for 72 hours. Group-1 (n=10) received aliskiren (60 mg/kg/day) dissolved in water by oral gavage starting one day before and continued throughout the period of UO until the terminal experiment 5 days post reversal when the renal functions were measured using clearance techniques. Group-2 (n=10) underwent similar protocol but had drinking water only. In addition, gene expression of some markers of kidney injury was measured in the kidney tissue using PCR technique. RESULTS The mean arterial blood pressure and heart rate in both groups were similar. UO affected all hemodynamic and tubular parameters in the affected kidney. So in Group-2, left RBF, was 57% of the right RBF (1.82±0.12 vs. 3.19±0.40, P<0.01). Similarly, left GFR was 55% that of the right GFR (0.81±0.08 vs. 1.44±0.09, P<0.01). On the other hand, the left fractional excretion of sodium (FENa) was higher than the right FENa (0.76±0.17 vs. 0.56±0.09, P<0.05). Aliskiren attenuated the UO-related alterations in hemodynamic parameters; so when the left obstructed kidney in Group-2 and Group-1 were compared, RBF was significantly higher in Group-1 (2.44±0.30 vs. 1.82±0.12, P=0.049). GFR was also higher in Group-1 (1.02±0.10 vs. 0.81±0.08, P=0.07) but did not reach statistical significance. On the other hand, the left renal FENa was similar in both groups (0.53±0.08 vs. 0.76±0.17, P=0.12). Aliskiren also decreased the gene expressions of some of the markers of kidney injury such as Lipocalin-2 (2.7±0.2 vs. 5.5±1.2, P=0.03). CONCLUSIONS Aliskiren attenuated the UO-induced alterations in the hemodynamic renal parameters and some of the markers of kidney injury but not the tubular alterations indicating an incomplete protective effect of this renin inhibitor © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e888 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Fayez Hammad More articles by this author Loay Lubbad More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...