Influence of the interaction between Ac‑SDKP and Ang II on the pathogenesis and development of silicotic fibrosis

Zhang,Yi; Yang,Fang; Liu,Yan; Peng,Hai‑Bing; Geng,Yu‑Cong; Li,Shi‑Feng; Xu,Hong; Zhu,Li‑Yan; Yang,Xiu‑Hong; Brann,Darrell

doi:10.3892/mmr.2018.8824

Influence of the interaction between Ac‑SDKP and Ang II on the pathogenesis and development of silicotic fibrosis

Authors:
- Yi Zhang
- Fang Yang
- Yan Liu
- Hai‑Bing Peng
- Yu‑Cong Geng
- Shi‑Feng Li
- Hong Xu
- Li‑Yan Zhu
- Xiu‑Hong Yang
- Darrell Brann
View Affiliations

Affiliations: Basic Medical College, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China, Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China, Ji Tang College, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Published online on: March 29, 2018 https://doi.org/10.3892/mmr.2018.8824
Pages: 7467-7476
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

N‑acetyl‑seryl‑aspartyl‑lysyl‑proline (Ac‑SDKP) is a natural tetrapeptide that is released from thymosin β4 by prolyl oligopeptides. It is hydrolyzed by the key enzyme of the renin‑angiotensin system, angiotensin‑converting enzyme (ACE). The aim of the present study was to investigate the alterations in Ac‑SDKP and the ACE/angiotensin II (Ang II)/angiotensin II type 1 (AT1) receptor axis and its impact on the pathogenesis and development of silicotic fibrosis. For in vivo studies, a HOPE MED 8050 exposure control apparatus was used to establish different stages of silicosis in a rat model treated with Ac‑SDKP. For in vitro studies, cultured primary lung fibroblasts were induced to differentiate into myofibroblasts by Ang II, and were pretreated with Ac‑SDKP and valsartan. The results of the present study revealed that, during silicosis development, ACE/Ang II/AT1 expression in local lung tissues increased, whereas that of Ac‑SDKP decreased. Ac‑SDKP and the ACE/AT1/Ang II axis were inversely altered in the development of silicotic fibrosis. Ac‑SDKP treatment had an anti‑fibrotic effect in vivo. Compared with the silicosis group, the expression of α‑smooth muscle actin (α‑SMA), Collagen (Col) I, Fibronectin (Fn) and AT1 were significantly downregulated, whereas matrix metalloproteinase‑1 (MMP‑1) expression and the MMP‑1/tissue inhibitor of metalloproteinases‑1 (TIMP‑1) ratio was increased in the Ac‑SDKP treatment group. In vitro, pre‑treatment with Ac‑SDKP or valsartan attenuated the expression of α‑SMA, Col I, Fn and AT1 in Ang II‑induced fibroblasts. In addition, MMP‑1 expression and the MMP‑1/TIMP‑1 ratio were significantly higher in Ac‑SDKP and valsartan pre‑treatment groups compared with the Ang II group. In conclusion, the results of the present study suggest that an imbalance between Ac‑SDKP and ACE/Ang II/AT1 molecules promotes the development of silicosis and that Ac‑SDKP protects against silicotic fibrosis by inhibiting Ang II‑induced myofibroblast differentiation and extracellular matrix production.

View Figures

View References

1	Rimal B, Greenberg AK and Rom WN: Basic pathogenetic mechanisms in silicosis: Current understanding. Curr Opin Pulm Med. 11:169–173. 2005. View Article : Google Scholar : PubMed/NCBI
2	Cavasin MA, Rhaleb NE, Yang XP and Carretero OA: Prolyl oligopeptidase is involved in release of the antifibrotic peptide Ac-SDKP. Hypertension. 43:1140–1145. 2004. View Article : Google Scholar : PubMed/NCBI
3	Mnguni AT, Engel ME, Borkum MS and Mayosi BM: The effects of angiotensin converting enzyme inhibitors (ACE-I) on human N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) levels: A systematic review and meta-analysis. PLoS One. 10:e01433382015. View Article : Google Scholar : PubMed/NCBI
4	Kumar N, Nakagawa P, Janic B, Romero CA, Worou ME, Monu SR, Peterson EL, Shaw J, Valeriote F, Ongeri EM, et al: The anti-inflammatory peptide Ac-SDKP is released from thymosin-β4 by renal meprin-α and prolyl oligopeptidase. Am J Physiol Renal Physiol. 310:F1026–F1034. 2016. View Article : Google Scholar : PubMed/NCBI
5	Meng Y, Yu CH, Li W, Li T, Luo W, Huang S, Wu PS, Cai SX and Li X: Angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-κB pathway. Am J Respir Cell Mol Biol. 50:723–736. 2014. View Article : Google Scholar : PubMed/NCBI
6	Ntsekhe M, Matthews K, Wolske J, Badri M, Wilkinson KA, Wilkinson RJ, Sturrock ED and Mayosi BM: Scientific letter: Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) and Galectin-3 levels in tuberculous pericardial effusion: Implications for pathogenesis and prevention of pericardial constriction. Heart. 98:1326–1328. 2012. View Article : Google Scholar : PubMed/NCBI
7	Wang J, Chen L, Chen B, Meliton A, Liu SQ, Shi Y, Liu T, Deb DK, Solway J and Li YC: Chronic activation of the renin-angiotensin system induces lung fibrosis. Sci Rep. 5:155612015. View Article : Google Scholar : PubMed/NCBI
8	Murphy AM, Wong AL and Bezuhly M: Modulation of angiotensin II signaling in the prevention of fibrosis. Fibrogenesis Tissue Repair. 8:72015. View Article : Google Scholar : PubMed/NCBI
9	Wei L, Alhenc-Gelas F, Corvol P and Clauser E: The two homologous domains of human angiotensin I-converting enzyme are both catalytically active. J Biol Chem. 266:9002–9008. 1991.PubMed/NCBI
10	Masuyer G, Schwager SL, Sturrock ED, Isaac RE and Acharya KR: Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides. Sci Rep. 2:7172012. View Article : Google Scholar : PubMed/NCBI
11	Stawski L, Han R, Bujor AM and Trojanowska M: Angiotensin II induces skin fibrosis: A novel mouse model of dermal fibrosis. Arthritis Res Ther. 14:R1942012. View Article : Google Scholar : PubMed/NCBI
12	Cavin S, Maric D and Diviani D: A-kinase anchoring protein-Lbc promotes pro-fibrotic signaling in cardiac fibroblasts. Biochim Biophys Acta. 1843:335–345. 2014. View Article : Google Scholar : PubMed/NCBI
13	Wong MH, Chapin OC and Johnson MD: LPS-stimulated cytokine production in type I cells is modulated by the renin-angiotensin system. Am J Respir Cell Mol Biol. 46:641–650. 2012. View Article : Google Scholar : PubMed/NCBI
14	Uhal BD, Kim JK, Li X and Molina-Molina M: Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: Autocrine mechanisms in myofibroblasts and macrophages. Curr Pharm Des. 13:1247–1256. 2007. View Article : Google Scholar : PubMed/NCBI
15	Masuyer G, Douglas RG, Sturrock ED and Acharya KR: Structural basis of Ac-SDKP hydrolysis by Angiotensin-I converting enzyme. Sci Rep. 5:137422015. View Article : Google Scholar : PubMed/NCBI
16	Liu Y, Xu H, Geng Y, Xu D, Zhang L, Yang Y, Wei Z, Zhang B, Li S, Gao X, et al: Dibutyryl-cAMP attenuates pulmonary fibrosis by blocking myofibroblast differentiation via PKA/CREB/CBP signaling in rats with silicosis. Respir Res. 18:382017. View Article : Google Scholar : PubMed/NCBI
17	Xu H, Yang F, Sun Y, Yuan Y, Cheng H, Wei Z, Li S, Cheng T, Brann D and Wang R: A new antifibrotic target of Ac-SDKP: Inhibition of myofibroblast differentiation in rat lung with silicosis. PLoS One. 7:e403012012. View Article : Google Scholar : PubMed/NCBI
18	Li S, Gao X, Xu D, Wang X, Liu Y, Zhang L, Deng H, Wei Z, Tian J, Xu H and Yang F: Inhibition effect of N-acetyl-seryl-aspartyl-lysyl-proline on myofibroblast differentiation by regulating acetylated tubulin α in silicotic rat model. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 33:816–821. 2015.(In Chinese). PubMed/NCBI
19	Meng Y, Li T, Zhou GS, Chen Y, Yu CH, Pang MX, Li W, Li Y, Zhang WY and Li X: The angiotensin-converting enzyme 2/angiotensin (1–7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway. Antioxid Redox Signal. 22:241–258. 2015. View Article : Google Scholar : PubMed/NCBI
20	Morimoto Y, Nagatomo H, Hirohashi M, Oyabu T, Ogami A, Yamato H, Kuroda K, Obata Y, Higashi T and Tanaka I: Expression of clara cell secretory protein in the lungs of rats exposed to crystalline silica in vivo. J Occup Health. 47:504–509. 2005. View Article : Google Scholar : PubMed/NCBI
21	Dong H, Jing W, Yabo Y, Xiaokang Y, Wan W, Min M, Wenyang W, Zhaoquan C, Yingru X and Rongbo Z: Establishment of rat model of silicotuberculosis and its pathological characteristic. Pathog Glob Health. 108:312–316. 2014. View Article : Google Scholar : PubMed/NCBI
22	Zhou B, Liu Y, Kahn M, Ann DK, Han A, Wang H, Nguyen C, Flodby P, Zhong Q, Krishnaveni MS, et al: Interactions between β-catenin and transforming growth factor-β signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem. 287:7026–7038. 2012. View Article : Google Scholar : PubMed/NCBI
23	Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, Shimokata K and Hasegawa Y: Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 43:161–172. 2010. View Article : Google Scholar : PubMed/NCBI
24	Marriott S, Baskir RS, Gaskill C, Menon S, Carrier EJ, Williams J, Talati M, Helm K, Alford CE, Kropski JA, et al: ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling. Am J Physiol Cell Physiol. 307:C684–C698. 2014. View Article : Google Scholar : PubMed/NCBI
25	Zolak JS, Jagirdar R, Surolia R, Karki S, Oliva O, Hock T, Guroji P, Ding Q, Liu RM, Bolisetty S, et al: Pleural mesothelial cell differentiation and invasion in fibrogenic lung injury. Am J Pathol. 182:1239–1247. 2013. View Article : Google Scholar : PubMed/NCBI
26	Tumelty KE, Smith BD, Nugent MA and Layne MD: Aortic carboxypeptidase-like protein (ACLP) enhances lung myofibroblast differentiation through transforming growth factor β receptor-dependent and -independent pathways. J Biol Chem. 289:2526–2536. 2014. View Article : Google Scholar : PubMed/NCBI
27	Specks U, Martin WJ II and Rohrbach MS: Bronchoalveolar lavage fluid angiotensin-converting enzyme in interstitial lung diseases. Am Rev Respir Dis. 141:117–123. 1990. View Article : Google Scholar : PubMed/NCBI
28	Li X, Molina-Molina M, Abdul-Hafez A, Ramirez J, Serrano-Mollar A, Xaubet A and Uhal BD: Extravascular sources of lung angiotensin peptide synthesis in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 291:L887–L895. 2006. View Article : Google Scholar : PubMed/NCBI
29	Bai J, Zhang N, Hua Y, Wang B, Ling L, Ferro A and Xu B: Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts. PLoS One. 8:e721202013. View Article : Google Scholar : PubMed/NCBI
30	Guo X, Yan F, Li J, Zhang C and Bu P: SIRT3 attenuates AngII-induced cardiac fibrosis by inhibiting myofibroblasts transdifferentiation via STAT3-NFATc2 pathway. Am J Transl Res. 9:3258–3269. 2017.PubMed/NCBI
31	Peng H, Carretero OA, Peterson EL and Rhaleb NE: Ac-SDKP inhibits transforming growth factor-beta1-induced differentiation of human cardiac fibroblasts into myofibroblasts. Am J Physiol Heart Circ Physiol. 298:H1357–H1364. 2010. View Article : Google Scholar : PubMed/NCBI
32	Pokharel S, Rasoul S, Roks AJ, van Leeuwen RE, van Luyn MJ, Deelman LE, Smits JF, Carretero O, van Gilst WH and Pinto YM: N-acetyl-Ser-Asp-Lys-Pro inhibits phosphorylation of Smad2 in cardiac fibroblasts. Hypertension. 40:155–161. 2002. View Article : Google Scholar : PubMed/NCBI
33	Kanasaki K, Koya D, Sugimoto T, Isono M, Kashiwagi A and Haneda M: N-Acetyl-seryl-aspartyl-lysyl-proline inhibits TGF-beta-mediated plasminogen activator inhibitor-1 expression via inhibition of Smad pathway in human mesangial cells. J Am Soc Nephrol. 14:863–872. 2003. View Article : Google Scholar : PubMed/NCBI
34	Lin CX, Rhaleb NE, Yang XP, Liao TD, D'Ambrosio MA and Carretero OA: Prevention of aortic fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol. 295:H1253–H1261. 2008. View Article : Google Scholar : PubMed/NCBI
35	Yamazaki KG, Gonzalez E and Zambon AC: Crosstalk between the renin-angiotensin system and the advance glycation end product axis in the heart: Role of the cardiac fibroblast. J Cardiovasc Transl Res. 5:805–813. 2012. View Article : Google Scholar : PubMed/NCBI
36	Samarakoon R, Overstreet JM and Higgins PJ: TGF-β signaling in tissue fibrosis: Redox controls, target genes and therapeutic opportunities. Cell Signal. 25:264–268. 2013. View Article : Google Scholar : PubMed/NCBI
37	Rosenkranz S: TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res. 63:423–432. 2004. View Article : Google Scholar : PubMed/NCBI
38	Craig VJ, Zhang L, Hagood JS and Owen CA: Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 53:585–600. 2015. View Article : Google Scholar : PubMed/NCBI
39	Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Yanase K, Namisaki T, Imazu H and Fukui H: Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse. Hepatology. 36:850–860. 2002. View Article : Google Scholar : PubMed/NCBI