Protective arms of the renin–angiotensin‐system in neurological disease

Sumners, Colin; Horiuchi, Masatsugu; Widdop, Robert E; McCarthy, Claudia A.; Unger, Thomas; Steckelings, Ulrike Muscha

doi:10.1111/1440-1681.12137

Cited by 78 publications

(51 citation statements)

References 76 publications

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“…AT2R and Mas are the most well characterize of these opposing or protective receptors with the Mas-related G-protein-coupled receptor (MrgD) as a more recently discovered candidate [27]. Most importantly, AT2R and Mas mediate a multitude of strikingly similar tissue protective and regenerative effects including anti-inflammatory, anti-fibrotic, neuroregenerative, vasodilatory, and beneficial metabolic effects [28–30]. …”

Section: Discussionmentioning

confidence: 99%

Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer

Pei

Mao

Wan

et al. 2017

J Exp Clin Cancer Res

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BackgroundBladder cancer (BCa) is the ninth most common form of cancer in the world. There is a continuing need not only for improving the accuracy of diagnostic markers but also for the development of new treatment strategies. Recent studies have shown that the renin-angiotensin system (RAS), which include the angiotensin type 1 (AT1R), type 2(AT2R), and Mas receptors, play an important role in tumorigenesis and may guide us in meeting those needs.ResultsIn this study, we first observed that AT1R and Mas expression levels were significantly upregulated in BCa specimens while AT2R was significantly downregulated. Viral vector mediated overexpression of AT2R induced apoptosis and dramatically suppressed BCa cell proliferation in vitro, suggesting a therapeutic effect. Investigation into the mechanism revealed that the overexpression of AT2R increases the expression levels of caspase-3, caspase-8, and p38 and decreases the expression level of pErk. AT2R overexpression also leads to upregulation of 2 apoptosis-related genes (BCL2A1, TNFSF25) and downregulation of 8 apoptosis-related genes (CASP 6, CASP 9, DFFA, IGF1R, PYCARD, TNF, TNFRSF21, TNFSF10, NAIP) in transduced EJ cells as determined by PCR Array analysis. In vivo, we observed that AT2R overexpression caused significant reduction in xenograft tumors sizes by downregulation VEGF and induction of apoptosis.ConclusionsTaken together, the data suggest that AT1R, AT2R or Mas could be used as a diagnostic marker of BCa and AT2R is a promising novel target gene for BCa gene therapy.

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Section: Discussionmentioning

confidence: 99%

Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer

Pei

Mao

Wan

et al. 2017

J Exp Clin Cancer Res

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“…New studies have elaborated on the hypothesis because the neuronal damage seen in stroke patients could be associated with increased activity of the angiotensin receptor subtype 1 in the brain-specific RAAS system, whereas the expression of the angiotensin receptor subtype 2 in contrast seems to exert neuroprotective effects. [28][29][30] An overactive RAAS systemwith hypokalemia as a possible pseudo marker-could, therefore, as a consequence potentiate subclinical strokes, resulting in more extensive neurological damage, worse symptoms, and subsidiarily more pronounced neurological deficits. The synergistic effect of mild hypokalemia and ESVEA could be a …”

Section: Discussionmentioning

confidence: 99%

Mild Hypokalemia and Supraventricular Ectopy Increases the Risk of Stroke in Community-Dwelling Subjects

Mattsson

Kumarathurai

Larsen

et al. 2017

Stroke

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Background and Purpose-Stroke is independently associated with the common conditions of hypokalemia and supraventricular ectopy, and we hypothesize that the combination of excessive supraventricular ectopic activity and hypokalemia has a synergistic impact on the prognosis in terms of stroke in the general population. Methods-Subjects (55-75 years old) from the Copenhagen Holter Study cohort (N=671) with no history of atrial fibrillation or stroke were studied-including baseline values of potassium and ambulatory 48-hour Holter monitoring. Excessive supraventricular ectopic activity is defined as ≥30 premature atrial complexes per hour or any episodes of runs of ≥20. Hypokalemia was defined as plasma-potassium ≤3.6 mmol/L. The primary end point was ischemic stroke. Cox models were used. Results-Hypokalemia was mild (mean, 3.4 mmol/L; range, 2.7-3.6). Hypokalemic subjects were older (67.0±6.94 versus 64.0±6.66 years; P<0.0001) and more hypertensive (165.1±26.1 versus 154.6±23.5 mm Hg; P<0.0001). Median followup time was 14.4 years (Q1-Q3, 9.4-14.7 years). The incidence of stroke was significantly higher in the hypokalemic group (hazard ratio, 1.84; 95% confidence interval, 1.04-3.28) after covariate adjustments, as well as in a competing risk analysis with death (hazard ratio, 1.51; 95% confidence interval, 1.12-2.04). Excessive supraventricular ectopic activity was also associated with stroke (hazard ratio, 2.23; 95% confidence interval, 1.33-3.76). The combination of hypokalemia and excessive supraventricular ectopic activity increased the risk of events synergistically. Stroke rate was 93 per 1000 patient-year (P<0.0001) in this group (n=17) compared with 6.9 (n=480); 11 (n=81), and 13 (n=93) per 1000 patient-year in the groups without the combination. Conclusions-The combination of hypokalemia and excessive supraventricular ectopy carries a poor prognosis in terms of stroke.

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“…Ang-(1-7), d-Ala7-Ang-(1-7), d-Pro7-Ang- (1)(2)(3)(4)(5)(6)(7) were from Biosynthan (Berlin, Germany). Adrenaline, forskolin, HOE 140 (icatibant), 3-isobutyl-1-methylxanthine (IBMX), isoproterenol, RPMI1640, trypsin/EDTA, phenylmethylsulfonyl fluoride (PMSF), protease inhibitor cocktail, and phosphatase inhibitor cocktail were purchased from Sigma Aldrich (St. Louise, MO).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…• We also generated double-knockout mice deficient in both Ang- (1)(2)(3)(4)(5)(6)(7) receptors, Mas and MrgD.…”

mentioning

confidence: 99%

G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

et al. 2016

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Angiotensin (Ang)-(1–7) has cardiovascular protective effects and is the opponent of the often detrimental Ang II within the renin–angiotensin system. Although it is well accepted that the G-protein–coupled receptor Mas is a receptor for the heptapeptide, the lack in knowing initial signaling molecules stimulated by Ang-(1–7) prevented definitive characterization of ligand/receptor pharmacology as well as identification of further hypothesized receptors for the heptapeptide. The study aimed to identify a second messenger stimulated by Ang-(1–7) allowing confirmation as well as discovery of the heptapeptide’s receptors. Ang-(1–7) elevates cAMP concentration in primary cells, such as endothelial or mesangial cells. Using cAMP as readout in receptor-transfected human embryonic kidney (HEK293) cells, we provided pharmacological proof that Mas is a functional receptor for Ang-(1–7). Moreover, we identified the G-protein–coupled receptor MrgD as a second receptor for Ang-(1–7). Consequently, the heptapeptide failed to increase cAMP concentration in primary mesangial cells with genetic deficiency in both Mas and MrgD . Mice deficient in MrgD showed an impaired hemodynamic response after Ang-(1–7) administration. Furthermore, we excluded the Ang II type 2 receptor as a receptor for the heptapeptide but discovered that the Ang II type 2 blocker PD123319 can also block Mas and MrgD receptors. Our results lead to an expansion and partial revision of the renin–angiotensin system, by identifying a second receptor for Ang-(1–7), by excluding Ang II type 2 as a receptor for the heptapeptide, and by enforcing the revisit of such publications which concluded Ang II type 2 function by only using PD123319.

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Protective arms of the renin–angiotensin‐system in neurological disease

Cited by 78 publications

References 76 publications

Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer

Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer

Mild Hypokalemia and Supraventricular Ectopy Increases the Risk of Stroke in Community-Dwelling Subjects

G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

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