Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway

Yu,Xiaozheng; Cui,Lijian; Hou,Fei; Liu,Xiaoya; Wang,Yan; Wen,Yan; Chi,Cheng; Li,Chunyun; Liu,Ruixia; Yin,Chenghong

doi:10.3892/ijmm.2017.3252

Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway

Authors:
- Xiaozheng Yu
- Lijian Cui
- Fei Hou
- Xiaoya Liu
- Yan Wang
- Yan Wen
- Cheng Chi
- Chunyun Li
- Ruixia Liu
- Chenghong Yin
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Affiliations: Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China, Department of Emergency, Beijing Chaoyang Hospital (Jingxi Campus), Capital Medical University, Beijing 100043, P.R. China, Department of Infectious Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China, Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
Published online on: November 13, 2017 https://doi.org/10.3892/ijmm.2017.3252
Pages: 409-420

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Abstract

The aim of the present study was to investigate the role of the angiotensin-converting enzyme (ACE)2-angiotensin‑(Ang)-(1-7)-Mas axis in the pathogenesis of pancreatitis and the association between this axis and the p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor (NF-κB) signaling pathway in pancreatic acinar cells. Mouse pancreatic acinar cancer (MPC-83) cells were stimulated with 10 nM caerulein (CAE) to create an in vitro model of acute pancreatitis, and collected for analysis at 2, 6, 12, 24 and 48 h post stimulation. In addition, cells were pretreated with different concentrations of Ang‑(1‑7), Ang‑(1‑7) antagonist A779, p38 MAPK inhibitor SB203580 or ACE2 inhibitor DX600 for 30 min, and then stimulated with CAE for 24 h. The ACE2, Mas receptor, p38 MAPK, phosphorylated (p)-p38 MAPK and NF-κB expression levels were evaluated using western blotting and immunofluorescence. p38 MAPK, NF-κB, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8 and IL-10 mRNA expression levels were assessed using reverse transcription-quantitative polymerase chain reaction. The results of the immunofluorescence assay demonstrated that ACE2 and p38 MAPK were present mainly in the cytoplasm, while the Mas receptor was located mainly in the cell membrane. ACE2, p38 MAPK and p-p38 MAPK protein levels were significantly increased (P<0.05) following stimulation with CAE compared with those in the control group and peaked at 24 h. Mas receptor protein levels were significantly upregulated (P<0.05) between 6 and 24 h, peaking at 12 h. Ang‑(1‑7) and SB203580 downregulated p-p38 MAPK and NF-κB expression and the mRNA levels of inflammatory factors IL-6, TNF-α and IL-8, but upregulated the mRNA level of inflammatory factor IL-10 compared with those treated with CAE alone. These results were supported by the opposite outcomes observed for cells treated with A779 or DX600. Therefore, it was concluded that the ACE2-Ang‑(1‑7)-Mas axis significantly inhibits pancreatitis by inhibition of the p38 MAPK/NF-κB signaling pathway.

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1	Akay C, Yaman H, Oztosun M, Cakir E, Yildirim AO, Eyi YE, Agilli M, Akgul EO, Aydin I, Kaldirim U, et al: The protective effects of taurine on experimental acute pancreatitis in a rat model. Hum Exp Toxicol. 32:522–529. 2013. View Article : Google Scholar : PubMed/NCBI
2	Pan Z, Feng L, Long H, Wang H, Feng J and Chen F: Effects of local pancreatic renin-angiotensin system on the microcirculation of rat with severe acute pancreatitis. Korean J Physiol Pharmacol. 19:299–307. 2015. View Article : Google Scholar : PubMed/NCBI
3	Singh P and Garg PK: Pathophysiological mechanisms in acute pancreatitis: Current understanding. Indian J Gastroenterol. 35:153–166. 2016. View Article : Google Scholar : PubMed/NCBI
4	Singh VK, Wu BU, Bollen TL, Repas K, Maurer R, Mortele KJ and Banks PA: Early systemic inflammatory response syndrome is associated with severe acute pancreatitis. Clin Gastroenterol Hepatol. 7:1247–1251. 2009. View Article : Google Scholar : PubMed/NCBI
5	Mofidi R, Duff MD, Wigmore SJ, Madhavan KK, Garden OJ and Parks RW: Association between early systemic inflammatory response, severity of multiorgan dysfunction and death in acute pancreatitis. Br J Surg. 93:738–744. 2006. View Article : Google Scholar : PubMed/NCBI
6	Liu M, Shi L, Chen M, Chen S and Zou X: Effects of c-Jun N-terminal kinase signaling pathway on severe acute pancreatitis-associated lung injury. Pancreas. 41:358–366. 2012. View Article : Google Scholar
7	van Santvoort HC, Bakker OJ, Bollen TL, Besselink MG, Ahmed Ali U, Schrijver AM, Boermeester MA, van Goor H, Dejong CH, van Eijck CH, et al Dutch Pancreatitis Study Group: A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome. Gastroenterology. 141:1254–1263. 2011. View Article : Google Scholar : PubMed/NCBI
8	Petrov MS, Shanbhag S, Chakraborty M, Phillips AR and Windsor JA: Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology. 139:813–820. 2010. View Article : Google Scholar : PubMed/NCBI
9	Gul R, Ramdas M, Mandavia CH, Sowers JR and Pulakat L: RAS-mediated adaptive mechanisms in cardiovascular tissues: Confounding factors of RAS blockade therapy and alternative approaches. Cardiorenal Med. 2:268–280. 2012. View Article : Google Scholar
10	Lenos MG and Tsaniklidou SM: Comment on 'Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice'. Hepatology. 51:7182010. View Article : Google Scholar
11	Verma A, Shan Z, Lei B, Yuan L, Liu X, Nakagawa T, Grant MB, Lewin AS, Hauswirth WW, Raizada MK, et al: ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy. Mol Ther. 20:28–36. 2012. View Article : Google Scholar :
12	Zhang XP, Li ZJ and Zhang J: Inflammatory mediators and microcirculatory disturbance in acute pancreatitis. Hepatobiliary Pancreat Dis Int. 8:351–357. 2009.PubMed/NCBI
13	Ibiş M, Yüksel O, Yilmaz G, Köklü S, Yilmaz FM, Ertuğrul I, Uçar E and Altiparmak ME: Serum angiotensin converting enzyme levels in pancreatic diseases. Hepatogastroenterology. 55:1814–1817. 2008.
14	Ulmasov B, Xu Z, Talkad V, Oshima K and Neuschwander-Tetri BA: Angiotensin II signaling through the AT1a and AT1b receptors does not have a role in the development of cerulein-induced chronic pancreatitis in the mouse. Am J Physiol Gastrointest Liver Physiol. 299:G70–G80. 2010. View Article : Google Scholar : PubMed/NCBI
15	Ahmadian E, Pennefather PS, Eftekhari A, Heidari R and Eghbal MA: Role of renin-angiotensin system in liver diseases: An outline on the potential therapeutic points of intervention. Expert Rev Gastroenterol Hepatol. 10:1279–1288. 2016. View Article : Google Scholar : PubMed/NCBI
16	Guo YJ, Li WH, Wu R, Xie Q and Cui LQ: ACE2 overexpression inhibits angiotensin II-induced monocyte chemoattractant protein-1 expression in macrophages. Arch Med Res. 39:149–154. 2008. View Article : Google Scholar : PubMed/NCBI
17	Verdecchia P, Gentile G, Angeli F and Reboldi G: Beyond blood pressure: Evidence for cardiovascular, cerebrovascular, and renal protective effects of renin-angiotensin system blockers. Ther Adv Cardiovasc Dis. 6:81–91. 2012. View Article : Google Scholar : PubMed/NCBI
18	Fraga-Silva RA, Da Silva DG, Montecucco F, Mach F, Stergiopulos N, da Silva RF and Santos RA: The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis: A potential target for treating thrombotic diseases. Thromb Haemost. 108:1089–1096. 2012. View Article : Google Scholar : PubMed/NCBI
19	Santos RA, Ferreira AJ, Verano-Braga T and Bader M: Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: New players of the renin-angiotensin system. J Endocrinol. 216:R1–R17. 2013. View Article : Google Scholar
20	Patel VB, Zhong JC, Grant MB and Oudit GY: Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res. 118:1313–1326. 2016. View Article : Google Scholar : PubMed/NCBI
21	Zhang Y, Liu J, Luo JY, Tian XY, Cheang WS, Xu J, Lau CW, Wang L, Wong WT, Wong CM, et al: Upregulation of Angiotensin- (1-7)-mediated signaling preserves endothelial function through reducing oxidative stress in diabetes. Antioxid Redox Signal. 23:880–892. 2015. View Article : Google Scholar : PubMed/NCBI
22	Márquez-Miranda V, Abrigo J, Rivera JC, Araya-Durán I, Aravena J, Simon F, Pacheco N, González-Nilo FD and Cabello- Verrugio C: The complex of PAMAM-OH dendrimer with Angiotensin-(1-7) prevented the disuse-induced skeletal muscle atrophy in mice. Int J Nanomedicine. 12:1985–1999. 2017. View Article : Google Scholar
23	Durand MJ, Zinkevich NS, Riedel M, Gutterman DD, Nasci VL, Salato VK, Hijjawi JB, Reuben CF, North PE and Beyer AM: Vascular actions of angiotensin 1-7 in the human microcirculation: Novel role for telomerase. Arterioscler Thromb Vasc Biol. 36:1254–1262. 2016. View Article : Google Scholar : PubMed/NCBI
24	Bihl JC, Zhang C, Zhao Y, Xiao X, Ma X and Chen Y, Chen S, Zhao B and Chen Y: Angiotensin-(1-7) counteracts the effects of Ang II on vascular smooth muscle cells, vascular remodeling and hemorrhagic stroke: Role of the NFкB inflammatory pathway. Vascul Pharmacol. 73:115–123. 2015. View Article : Google Scholar : PubMed/NCBI
25	Oruc N, Ozutemiz O, Nart D, Yuce G, Celik HA and Ilter T: Inhibition of renin-angiotensin system in experimental acute pancreatitis in rats: A new therapeutic target? Exp Toxicol Pathol. 62:353–360. 2010. View Article : Google Scholar
26	Wang Y, Wang J, Liu R, Qi H, Wen Y, Sun F and Yin C: Severe acute pancreatitis is associated with upregulation of the ACE2-angiotensin-(1-7)-Mas axis and promotes increased circulating angiotensin-(1-7). Pancreatology. 12:451–457. 2012. View Article : Google Scholar : PubMed/NCBI
27	Liu R, Qi H, Wang J, Wang Y, Cui L, Wen Y and Yin C: Angiotensin-converting enzyme (ACE and ACE2) imbalance correlates with the severity of cerulein-induced acute pancreatitis in mice. Exp Physiol. 99:651–663. 2014. View Article : Google Scholar : PubMed/NCBI
28	Liu R, Qi H, Wang J, Wang Y, Cui L, Wen Y and Yin C: Ulinastatin activates the renin-angiotensin system to ameliorate the pathophysiology of severe acute pancreatitis. J Gastroenterol Hepatol. 29:1328–1337. 2014. View Article : Google Scholar : PubMed/NCBI
29	Hemi R, Yochananov Y, Barhod E, Kasher-Meron M, Karasik A, Tirosh A and Kanety H: p38 mitogen-activated protein kinase-dependent transactivation of ErbB receptor family: A novel common mechanism for stress-induced IRS-1 serine phosphorylation and insulin resistance. Diabetes. 60:1134–1145. 2011. View Article : Google Scholar : PubMed/NCBI
30	Gao SC, Yin HB, Liu HX and Sui YH: Research progress on MAPK signal pathway in the pathogenesis of osteoarthritis. Zhongguo Gu Shang. 27:441–444. 2014.In Chinese. PubMed/NCBI
31	Ono K and Han J: The p38 signal transduction pathway: Activation and function. Cell Signal. 12:1–13. 2000. View Article : Google Scholar : PubMed/NCBI
32	Hu H, Zhu X, Lin R, Li Z and Chen L: Suppressive effects of Gua Lou Gui Zhi decoction on MCAO-induced NO and PGE2 production are dependent on the MAPK and NF-κB signaling pathways. Mol Med Rep. 14:5141–5147. 2016. View Article : Google Scholar : PubMed/NCBI
33	Moreno JA, Sullivan KA, Carbone DL, Hanneman WH and Tjalkens RB: Manganese potentiates nuclear factor-kappaB-dependent expression of nitric oxide synthase 2 in astrocytes by activating soluble guanylate cyclase and extracellular responsive kinase signaling pathways. J Neurosci Res. 86:2028–2038. 2008. View Article : Google Scholar : PubMed/NCBI
34	Carter AB and Hunninghake GW: A constitutive active MEK→ERK pathway negatively regulates NF-kappa B-dependent gene expression by modulating TATA-binding protein phosphorylation. J Biol Chem. 275:27858–27864. 2000.PubMed/NCBI
35	Williard DE, Twait E, Yuan Z, Carter AB and Samuel I: Nuclear factor kappa B-dependent gene transcription in cholecystokinin-and tumor necrosis factor-alpha-stimulated isolated acinar cells is regulated by p38 mitogen-activated protein kinase. Am J Surg. 200:283–290. 2010. View Article : Google Scholar : PubMed/NCBI
36	Twait E, Williard DE and Samuel I: Dominant negative p38 mitogen-activated protein kinase expression inhibits NF-kappaB activation in AR42J cells. Pancreatology. 10:119–128. 2010. View Article : Google Scholar : PubMed/NCBI
37	Yu JH, Lim JW and Kim H: Altered gene expression in cerulein-stimulated pancreatic acinar cells: Pathologic mechanism of acute pancreatitis. Korean J Physiol Pharmacol. 13:409–416. 2009. View Article : Google Scholar
38	Rolny P, Arlebäck A, Funch-Jensen P, Kruse A, Ravnsbaeck J and Järnerot G: Paradoxical response of sphincter of Oddi to intravenous injection of cholecystokinin or ceruletide. Manometric findings and results of treatment in biliary dyskinesia. Gut. 27:1507–1511. 1986. View Article : Google Scholar : PubMed/NCBI
39	Cui L, Liu R, Li C, Yu X, Liu X, Hou F, Chi C, Yin C and Wang C: Angiotensin (1-7) attenuates caerulein induced pancreatic acinar cell apoptosis. Mol Med Rep. 16:3455–3460. 2017.PubMed/NCBI
40	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
41	Tsang SW, Ip SP and Leung PS: Prophylactic and therapeutic treatments with AT 1 and AT 2 receptor antagonists and their effects on changes in the severity of pancreatitis. Int J Biochem Cell Biol. 36:330–339. 2004. View Article : Google Scholar
42	Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, et al: Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 277:14838–14843. 2002. View Article : Google Scholar : PubMed/NCBI
43	Ren T, He H, Yu X, Fan J, Tan J and Liu J: Angiotensin-(1-7) inhibits hypoxia-induced renal tubular epithelial-to-mesenchymal transition in rats. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 29:593–596. 2013.In Chinese. PubMed/NCBI
44	Su Z, Zimpelmann J and Burns KD: Angiotensin-(1-7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells. Kidney Int. 69:2212–2218. 2006. View Article : Google Scholar : PubMed/NCBI
45	Pérez S, Pereda J, Sabater L and Sastre J: Redox signaling in acute pancreatitis. Redox Biol. 5:1–14. 2015. View Article : Google Scholar : PubMed/NCBI
46	Lee WS, Shin JS, Jang DS and Lee KT: Cnidilide, an alkylphthalide isolated from the roots of Cnidium officinale, suppresses LPS-induced NO, PGE2, IL-1β, IL-6 and TNF-α production by AP-1 and NF-κB inactivation in RAW 264.7 macrophages. Int Immunopharmacol. 40:146–155. 2016. View Article : Google Scholar : PubMed/NCBI
47	Makhija R and Kingsnorth AN: Cytokine storm in acute pancreatitis. J Hepatobiliary Pancreat Surg. 9:401–410. 2002. View Article : Google Scholar : PubMed/NCBI
48	Ren HB, Li ZS, Xu GM, Tu ZX, Shi XG, Jia YT and Gong YF: Dynamic changes of mitogen-activated protein kinase signal transduction in rats with severe acute pancreatitis. Chin J Dig Dis. 5:123–125. 2004. View Article : Google Scholar : PubMed/NCBI
49	Xu M, Wang KN, Wu K and Wang XP: Pyrrolidine dithiocarbamate inhibits nuclear factor κB and Toll-like receptor 4 expression in rats with acute necrotizing pancreatitis. Gut Liver. 9:411–416. 2015. View Article : Google Scholar
50	Vaquero E, Gukovsky I, Zaninovic V, Gukovskaya AS and Pandol SJ: Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis. Am J Physiol Gastrointest Liver Physiol. 280:G1197–G1208. 2001. View Article : Google Scholar : PubMed/NCBI
51	Bettaieb A, Xi Y, Hosein E, Coggins N, Bachaalany S, Wiede F, Perez S, Griffey SM, Sastre J, Tiganis T, et al: Pancreatic T cell protein-tyrosine phosphatase deficiency ameliorates cerulein- induced acute pancreatitis. Cell Commun Signal. 12:132014. View Article : Google Scholar
52	Li G, Wu X, Yang L, He Y, Liu Y, Jin X and Yuan H: [Corrigendum] TLR4-mediated NF-κB signaling pathway mediates HMGB1-induced pancreatic injury in mice with severe acute pancreatitis. Int J Mol Med. 38:13132016. View Article : Google Scholar
53	Shi Q, Liao KS, Zhao KL, Wang WX, Zuo T, Deng WH, Chen C, Yu J, Guo WY, He XB, et al: Hydrogen-rich saline attenuates acute renal injury in sodium taurocholate-induced severe acute pancreatitis by inhibiting ROS and NF-κB pathway. Mediators Inflamm. 2015:6850432015. View Article : Google Scholar
54	Yang X, Jin H, Liu K, Gu Q and Xu X: A novel peptide derived from human pancreatitis-associated protein inhibits inflammation in vivo and in vitro and blocks NF-kappa B signaling pathway. PLoS One. 6:e291552011. View Article : Google Scholar : PubMed/NCBI
55	Steinle AU, Weidenbach H, Wagner M, Adler G and Schmid RM: NF-kappaB/Rel activation in cerulein pancreatitis. Gastroenterology. 116:420–430. 1999. View Article : Google Scholar : PubMed/NCBI
56	Kefaloyianni E, Gaitanaki C and Beis I: ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-kappaB transactivation during oxidative stress in skeletal myoblasts. Cell Signal. 18:2238–2251. 2006. View Article : Google Scholar : PubMed/NCBI
57	Saccani S, Pantano S and Natoli G: p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol. 3:69–75. 2002. View Article : Google Scholar