Kisspeptin‑13 inhibits bleomycin‑induced pulmonary fibrosis through GPR54 in mice

Lei,Zelin; Bai,Xue; Ma,Jianxiu; Yu,Qin

doi:10.3892/mmr.2019.10341

Kisspeptin‑13 inhibits bleomycin‑induced pulmonary fibrosis through GPR54 in mice

Authors:
- Zelin Lei
- Xue Bai
- Jianxiu Ma
- Qin Yu
View Affiliations

Affiliations: Department of Respiration, Key Laboratory of Biotherapy and Regenerative Medicine, First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China, Medical College, Northwest Minzu University, Lanzhou, Gansu 730030, P.R. China
Published online on: June 5, 2019 https://doi.org/10.3892/mmr.2019.10341
Pages: 1049-1056
Copyright: © Lei 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

Kisspeptin (KP) is an amidated neurohormone that is encoded by the KiSS‑1 metastasis suppressor (KISS1) gene and serves as the endogenous ligand for G protein‑coupled receptor 54 (GPR54). KP is involved in the regulation of several biological functions, such as reproduction, cancer and atherogenesis. Recent data suggested that KP may induce atherosclerotic plaque progression and instability, which may be reversed by the GPR54 antagonist KP‑234. Despite the KISS1 gene being previously reported as a downstream target of the classic transforming growth factor (TGF)/Smad2 signaling pathway, its role in fibrosis remains elusive. The purpose of the present study was to evaluate the role of KP‑13 (a product of the KISS1 gene) in a bleomycin (BLM)‑induced idiopathic pulmonary fibrosis model. Lung tissue samples were evaluated by quantitative PCR analysis, western blotting and ELISA. Daily intraperitoneal administration of KP‑13 significantly ameliorated body weight loss, histopathological lung abnormalities and pulmonary collagen deposition induced by BLM. Furthermore, KP‑13 downregulated the expression levels of tumor necrosis factor‑α, TGF‑β, collagen type I α1, actin α2 and matrix metalloproteinase 2 in BLM‑treated lungs compared with BLM group. Notably, the production of α‑smooth muscle actin in lung tissues, as well as the pulmonary levels of TGF‑β1 and phosphorylated‑Smad2/3, was reduced following treatment with KP‑13. The anti‑fibrotic effects of KP‑13 were reversed by KP‑234 (an antagonist of GPR54), but not by Cetrorelix (an antagonist of the gonadotropin‑releasing hormone receptor). Furthermore, apoptosis‑related proteins, such as Bax and caspase‑3, were decreased, whereas Bcl‑2 was markedly increased as determined by western blotting. Collectively, these data suggested that the KP/GPR54 signaling pathway may be a promising target for the treatment of idiopathic pulmonary fibrosis.

View Figures

View References

1	Ferrara G, Luppi F, Birring SS, Cerri S, Caminati A, Sköld M and Kreuter M: Best supportive care for idiopathic pulmonary fibrosis: Current gaps and future directions. Eur Respir Rev. 27(pii): 1700762018. View Article : Google Scholar : PubMed/NCBI
2	Xie Y, Wang JJ, Li GY, Li XL and Li JS: Acupuncture for idiopathic pulmonary fibrosis: Protocol for a systematic review. Medicine (Baltimore). 96:e91142017. View Article : Google Scholar : PubMed/NCBI
3	Sime PJ: The antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis. J Investig Med. 56:534–538. 2008. View Article : Google Scholar : PubMed/NCBI
4	Selman M, King TE and Pardo A; American Thoracic Society; European Respiratory Society; American College of Chest Physicians, : Idiopathic pulmonary fibrosis: Prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 134:136–151. 2001. View Article : Google Scholar : PubMed/NCBI
5	Tian J, Al-Odaini AA, Wang Y, Korah J, Dai M, Xiao L, Ali S and Lebrun JJ: KiSS1 gene as a novel mediator of TGFβ-mediated cell invasion in triple negative breast cancer. Cell Signal. 42:1–10. 2018. View Article : Google Scholar : PubMed/NCBI
6	Skorupskaite K, George JT and Anderson RA: The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update. 20:485–500. 2014. View Article : Google Scholar : PubMed/NCBI
7	Mead EJ, Maguire JJ, Kuc RE and Davenport AP: Kisspeptins are novel potent vasoconstrictors in humans, with a discrete localization of their receptor, G protein-coupled receptor 54, to atherosclerosis-prone vessels. Endocrinology. 148:140–147. 2007. View Article : Google Scholar : PubMed/NCBI
8	Jiang J, Jin W, Peng Y, He Z, Wei L, Li S, Wang X, Chang M and Wang R: In vivo and vitro characterization of the effects of kisspeptin-13, endogenous ligands for GPR54, on mouse gastrointestinal motility. Eur J Pharmacol. 794:216–223. 2017. View Article : Google Scholar : PubMed/NCBI
9	Jiang JH, He Z, Peng YL, Jin WD, Wang Z, Han RW, Chang M and Wang R: Kisspeptin-13 enhances memory and mitigates memory impairment induced by Aβ1–42 in mice novel object and object location recognition tasks. Neurobiol Learn Mem. 123:187–195. 2015. View Article : Google Scholar : PubMed/NCBI
10	Stathaki M, Armakolas A, Dimakakos A, Kaklamanis L, Vlachos I, Konstantoulakis MM, Zografos G and Koutsilieris M: Kisspeptin effect on endothelial monocyte activating polypeptide II (EMAP-II)-associated lymphocyte cell death and metastases in colorectal cancer patients. Mol Med. 20:80–92. 2014. View Article : Google Scholar : PubMed/NCBI
11	Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, et al: The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 276:34631–34636. 2001. View Article : Google Scholar : PubMed/NCBI
12	Meresman GF, Bilotas M, Buquet RA, Barañao RI, Sueldo C and Tesone M: Gonadotropin-releasing hormone agonist induces apoptosis and reduces cell proliferation in eutopic endometrial cultures from women with endometriosis. Fertility and sterility. 80 (Suppl 2):S702–S707. 2003. View Article : Google Scholar
13	Castellon E, Clementi M, Hitschfeld C, Sánchez C, Benítez D, Sáenz L, Contreras H and Huidobro C: Effect of leuprolide and cetrorelix on cell growth, apoptosis, and GnRH receptor expression in primary cell cultures from human prostate carcinoma. Cancer Invest. 24:261–268. 2006. View Article : Google Scholar : PubMed/NCBI
14	Kyritsi K, Meng F, Zhou T, Wu N, Venter J, Francis H, Kennedy L, Onori P, Franchitto A, Bernuzzi F, et al: Knockdown of hepatic gonadotropin-releasing hormone by vivo-morpholino decreases liver fibrosis in multidrug resistance gene 2 knockout mice by down-regulation of miR-200b. Am J Pathol. 187:1551–1565. 2017. View Article : Google Scholar : PubMed/NCBI
15	McMillin M, DeMorrow S, Glaser S, Venter J, Kyritsi K, Zhou T, Grant S, Giang T, Greene JF Jr, Wu N, et al: Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats. Am J Physiol Gastrointest Liver Physiol. 313:G410–G418. 2017. View Article : Google Scholar : PubMed/NCBI
16	Tian SL, Yang Y, Liu XL and Xu QB: Emodin attenuates bleomycin-induced pulmonary fibrosis via anti-inflammatory and Anti-oxidative activities in rats. Med Sci Monit. 24:1–10. 2018. View Article : Google Scholar : PubMed/NCBI
17	Luque RM, Kineman RD and Tena-Sempere M: Regulation of hypothalamic expression of KiSS-1 and GPR54 genes by metabolic factors: Analyses using mouse models and a cell line. Endocrinology. 148:4601–4611. 2007. View Article : Google Scholar : PubMed/NCBI
18	Wei YR, Qiu H, Wu Q, Du YK, Yin ZF, Chen SS, Jin YP, Zhao MM, Wang C, Weng D and Li HP: Establishment of the mouse model of acute exacerbation of idiopathic pulmonary fibrosis. Exp Lung Res. 42:75–86. 2016. View Article : Google Scholar : PubMed/NCBI
19	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 : PubMed/NCBI
20	Dong J and Ma Q: TIMP1 promotes multi-walled carbon nanotube-induced lung fibrosis by stimulating fibroblast activation and proliferation. Nanotoxicology. 11:41–51. 2017. View Article : Google Scholar : PubMed/NCBI
21	Waisberg DR, Parra ER, Barbas-Filho JV, Fernezlian S and Capelozzi VL: Increased fibroblast telomerase expression precedes myofibroblast α-smooth muscle actin expression in idiopathic pulmonary fibrosis. Clinics. 67:1039–1046. 2012. View Article : Google Scholar : PubMed/NCBI
22	Sun KH, Chang Y, Reed NI and Sheppard D: α-Smooth muscle actin is an inconsistent marker of fibroblasts responsible for force-dependent TGFβ activation or collagen production across multiple models of organ fibrosis. Am J Physiol Lung Cell Mol Physiol. 310:L824–L836. 2016. View Article : Google Scholar : PubMed/NCBI
23	Cetkovic A, Miljic D, Ljubić A, Patterson M, Ghatei M, Stamenković J, Nikolic-Djurovic M, Pekic S, Doknic M, Glišić A, et al: Plasma kisspeptin levels in pregnancies with diabetes and hypertensive disease as a potential marker of placental dysfunction and adverse perinatal outcome. Endocr Res. 37:78–88. 2012. View Article : Google Scholar : PubMed/NCBI
24	Hussain MA, Song WJ and Wolfe A: There is Kisspeptin - and then there is Kisspeptin. Trends Endocrinol Metab. 26:564–572. 2015. View Article : Google Scholar : PubMed/NCBI
25	Jayasena CN, Nijher GM, Comninos AN, Abbara A, Januszewki A, Vaal ML, Sriskandarajah L, Murphy KG, Farzad Z, Ghatei MA, et al: The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans. J Clin Endocrinol Metab. 96:E1963–E1972. 2011. View Article : Google Scholar : PubMed/NCBI
26	Zank DC, Bueno M, Mora AL and Rojas M: Idiopathic pulmonary fibrosis: Aging, mitochondrial dysfunction and cellular bioenergetics. Front Med (Lausanne). 5:102018. View Article : Google Scholar : PubMed/NCBI
27	Sava P, Ramanathan A, Dobronyi A, Peng X, Sun H, Ledesma-Mendoza A, Herzog EL and Gonzalez AL: Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung. JCI Insight. 2(pii): 963522017. View Article : Google Scholar : PubMed/NCBI
28	Sato K, Shirai R, Hontani M, Shinooka R, Hasegawa A, Kichise T, Yamashita T, Yoshizawa H, Watanabe R, Matsuyama TA, et al: Potent vasoconstrictor Kisspeptin-10 induces atherosclerotic plaque progression and instability: Reversal by its receptor GPR54 antagonist. J Am Heart Assoc. 6(pii): e0057902017.PubMed/NCBI
29	Oruqaj G, Karnati S, Vijayan V, Kotarkonda LK, Boateng E, Zhang W, Ruppert C, Günther A, Shi W and Baumgart-Vogt E: Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-β signaling. Proc Natl Acad Sci USA. 112:E2048–E2057. 2015. View Article : Google Scholar : PubMed/NCBI
30	Cutroneo KR, White SL, Phan SH and Ehrlich HP: Therapies for bleomycin induced lung fibrosis through regulation of TGF-beta1 induced collagen gene expression. J Cell Physiol. 211:585–589. 2007. View Article : Google Scholar : PubMed/NCBI