The ACE2-Angiotensin-(1–7)-Mas Axis Protects Against Pancreatic Cell Damage in Cell Culture

Wang, Jing; Liu, Ruixia; Qi, Haifeng; Wang, Yan; Cui, Lijian; Wen, Yiping; Li, Huihui; Yin, Chenghong

doi:10.1097/mpa.0000000000000247

Cited by 31 publications

(26 citation statements)

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“…The results demonstrated that Ang-(1-7) possessed the potential to inhibit apoptosis and protect the pancreas from damage. These data, together with a previous study (27), demonstrated that exogenous Ang-(1-7) may affect the balance of Ang-(1-7)/Ang II in addition to ACE2/ACE in AP. This is also consistent with previous animal experiments; that identified that ulinastatin significantly ameliorated pancreatic pathology through upregulating ACE2 and Ang (1-7) in addition to the serum biochemistry indicators of CAE-induced SAP mice (28).…”

Section: Discussionsupporting

confidence: 78%

“…Previous studies have demonstrated that the classic angiotensin-converting enzyme-angiotensin II type 1 receptor (ACE-Ang II-AT1) axis activity increases and may aggravate the development of pancreatitis (12)(13)(14). Studies have demonstrated that ACE2-Ang-(1-7)-Mas [ACE2-Ang-(1-7)-Mas] axis, the non-classical and the depressor renin-Ang system (RAS) pathway, possess adverse effects in numerous diseases and may be therapeutically useful (15,16). However, little is known about the potential roles of ACE2-Ang-(1-7)-Mas in apoptosis, and its precise method of regulation in any organ system.…”

Section: Introductionmentioning

confidence: 99%

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Angiotensin-(1–7) attenuates caerulein-induced pancreatic acinar cell apoptosis

Cui

Liu

et al. 2017

Molecular Medicine Reports

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Extensive apoptosis of pancreatic acinar cells frequently occurs in acute pancreatitis (AP), and has been identified to be closely associated with the decrease of pancreatic parenchymal cells and pancreatic damage. The present study aimed to investigate the possible effect of angiotensin (Ang)-(1-7) on caerulein (CAE)-induced pancreatic acinar cell apoptosis. Mouse pancreatic acinar cancer cells (MPC-83) were divided into 4 groups: Control group; CAE group; CAE + Ang-(1-7) group; and CAE + Ang-(1-7) antagonist (A779) group. The control group consisted of normal MPC-83 cells without special treatment. The CAE group was stimulated with 10 nmol/l CAE and harvested at 2, 6, 12, 24 and 48 h. For the CAE + Ang-(1-7) group and CAE + A779 group, the CAE-induced pancreatic acinar cells were mock pretreated or pretreated with different concentrations of Ang-(1-7) or A779 (10-7 , 10-6 or 10-5 mol/l) for 30 min. Caspase-3 is a critical executioner of apoptosis, as it is either partly or completely responsible for the proteolytic cleavage of numerous key proteins including the nuclear enzyme poly (ADP-ribose) polymerase. Activation of caspase-3 requires proteolytic processing of its inactive zymogen into activated p17 and p12 fragments. Thus, the present study investigated the apoptotic markers, including cleaved caspase-3, B-cell lymphoma 2 (Bcl-2), Bcl-2-like protein 4 (Bax) and renin-angiotensin system (RAS) pathway related proteins (ACE2 and Mas receptor). The results demonstrated that the cleaved caspase-3 levels were increased in the CAE group (P<0.05), peaking at 24 h, and declined when incubated with Ang-(1-7). Following treatment with Ang-(1-7), levels of the anti-apoptotic protein Bcl-2 rose dramatically in a dose-dependent manner. The ratio of the pro-apoptotic protein Bax to the anti-apoptotic protein Bcl-2 dropped notably, which demonstrated a tendency towards curbing apoptosis. In addition, the cleaved caspase-3 levels, and the ratio of Bax to Bcl-2 in the CAE + A779 group presented a significant rise compared with the CAE group. It was concluded that Ang-(1-7) may possess an inhibitory effect on CAE-induced pancreatic acinar cell apoptosis and that appropriate interventions in RAS may attenuate pancreatic injury during AP.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Angiotensin-(1–7) attenuates caerulein-induced pancreatic acinar cell apoptosis

Cui

Liu

et al. 2017

Molecular Medicine Reports

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“…Our previous study demonstrated that Ang 1–7 and its receptor Mas are expressed within AR42J cells ( 6 ). The effect of A779 on CAE-induced TLR4 and NF-κB expression was investigated in AR42J cells pretreated with various concentrations of A779 followed by CAE treatment for 12 h. Relative expression levels of TLR4 and NF-κB were determined by western blot analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Ang 1–7 has been reported to serve as an endogenous antagonist of Ang II, possessing anti-inflammatory and vasodilatory activities, and exerting protective effects against endothelial injury ( 3 – 5 ). Our previous study revealed that caerulein (CAE) can stimulate the ACE2-Ang-1-7-Mas axis and significantly inhibit pancreatitis development via endothelial nitric oxide synthase activation and nitric oxide signaling within AR42J cells ( 6 ). In addition, further study identified that in the AR42J cells stimulated by CAE, blocking of Mas receptor using A779, then enhancement of Ang ( 1 – 7 ), still can reduce the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin 1-7 ameliorates caerulein-induced inflammation in pancreatic acinar cells by downregulating Toll-like receptor 4/nuclear factor-κB expression

Wang

Cui

et al. 2017

Mol Med Report

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The present study aimed to investigate the effects of angiotensin (Ang) 1–7 on caerulein (CAE)-stimulated nuclear factor (NF)-κB, Toll-like receptor (TLR4) and cytokine expression using pancreatic acinar AR42J cells. AR42J cells were treated with 10 nmol/l CAE for various durations. In addition, cells were pretreated with various concentrations of Ang 1–7 or A779, a specific antagonist of Ang 1–7, and were stimulated with CAE for 12 h. Control cells were treated with vehicle (F-12K complete medium with 2% fetal bovine serum, 10 U/ml penicillin and 100 mg/ml streptomycin) alone. The mRNA and protein expression levels of TLR4, NF-κB, interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α) were determined by western blotting, immunofluorescence and reverse transcription-quantitative polymerase chain reaction. CAE treatment stimulated TLR4 and NF-κB expression within AR42J cells. Immunofluorescence indicated that TLR4 was expressed on the membranes and in the cytoplasm of AR42J cells, whereas NF-κB expression accumulated in the cytoplasm and nuclei. CAE-induced expression of TLR4 and NF-κB within AR42J cells was abrogated by 10−5 mmol/l Ang 1–7; however, TLR4 and NF-κB expression was enhanced with the addition of A779, particularly 10−5 mmol/l. In addition, treatment with 10−6 and 10−5 mmol/l Ang 1–7 significantly mitigated CAE-induced expression of IL-6, IL-8 and TNF-α, whereas it enhanced IL-10 expression. Conversely, A779 treatment enhanced the CAE-induced expression of IL-6, IL-8 and TNF-α, and reduced IL-10 expression in AR42J cells. In conclusion, these results suggested that Ang 1–7 may attenuate CAE-induced inflammation by downregulating TLR4, NF-κB and proinflammatory cytokine expression within AR42J cells. Therefore, Ang 1–7 may exert protective effects against the pathological progression of AP in a cell model of AP induced by CAE and may be considered in the development of treatments for this disease.

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“…In experimental disease models Ang(1–7)/MAS1 signalling suppress AngII‐induced pathogenesis. For example, AngII‐induced ROS overproduction and apoptosis in cerebral endothelial cells (Xiao et al, ), phosphorylation of c‐Src and MAPKs, leading to production of TGF‐β1 and collagen in cardiac fibroblasts (Meng et al, ; Tao et al, ; Zheng et al, ), muscle atrophy of gastrocnemius (Cisternas et al, ), pancreatic cell damage (Wang et al, ), ICAM‐1, VCAM‐1, and MCP‐1 expression in HUVECs (Liang et al, ,b) is suppressed by Ang(1–7) activated MAS1 receptors.…”

Section: Signallingmentioning

confidence: 99%

Significance of angiotensin 1–7 coupling with MAS1 receptor and other GPCRs to the renin‐angiotensin system: IUPHAR Review 22

Karnik

Singh

Tirupula

et al. 2017

British J Pharmacology

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This paper, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittees for the angiotensin receptors, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions, and their likely physiological roles in health and disease. More information on these receptor families can be found in the Concise Guide to PHARMACOLOGY Angiotensins are a group of hormonal peptides and include angiotensin II and angiotensin 1-7 produced by the renin angiotensin system. The biology, pharmacology and biochemistry of the receptors for angiotensins were extensively reviewed recently. In the review, the receptor nomenclature committee was not emphatic on designating MAS1 as the angiotensin 1-7 receptor on the basis of lack of classical G protein signalling and desensitization in response to angiotensin 1-7, as well as a lack of consensus on confirmatory ligand pharmacological analyses. A review of recent publications (2013-2016) on the rapidly progressing research on angiotensin 1-7 revealed that MAS1 and two additional receptors can function as 'angiotensin 1-7 receptors', and this deserves further consideration. In this review we have summarized the information on angiotensin 1-7 receptors and their crosstalk with classical angiotensin II receptors in the context of the functions of the renin angiotensin system. It was concluded that the receptors for angiotensin II and angiotensin 1-7 make up a sophisticated cross-regulated signalling network that modulates the endogenous protective and pathogenic facets of the renin angiotensin system.

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The ACE2-Angiotensin-(1–7)-Mas Axis Protects Against Pancreatic Cell Damage in Cell Culture

Abstract: ACE2-angiotensin-(1-7)-Mas axis significantly inhibits pancreatitis in response to decreased inflammatory factors by the activation of endothelial nitric oxide synthase and NO signaling pathways.

Cited by 31 publications

References 50 publications

Angiotensin-(1–7) attenuates caerulein-induced pancreatic acinar cell apoptosis

Angiotensin-(1–7) attenuates caerulein-induced pancreatic acinar cell apoptosis

Angiotensin 1-7 ameliorates caerulein-induced inflammation in pancreatic acinar cells by downregulating Toll-like receptor 4/nuclear factor-κB expression

Significance of angiotensin 1–7 coupling with MAS1 receptor and other GPCRs to the renin‐angiotensin system: IUPHAR Review 22

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