CTRP9 decreases high glucose‑induced trophoblast cell damage by reducing endoplasmic reticulum stress

Zhang,Lianxiao; Ding,Huiqing; Shi,Yubo; Zhang,Duoyi; Yang,Xue

doi:10.3892/mmr.2022.12701

CTRP9 decreases high glucose‑induced trophoblast cell damage by reducing endoplasmic reticulum stress

Authors:
- Lianxiao Zhang
- Huiqing Ding
- Yubo Shi
- Duoyi Zhang
- Xue Yang
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Ningbo First Hospital, Ningbo, Zhejiang 315000, P.R. China
Published online on: March 28, 2022 https://doi.org/10.3892/mmr.2022.12701
Article Number: 185
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

C1q/TNF‑α‑related protein 9 (CTRP9) is downregulated in gestational diabetes mellitus (GDM) and may exert a protective effect against GDM, although its mechanism of action is yet to be elucidated. To investigate the specific role of CTRP9 in GDM, the human placental trophoblast cell line HTR8/SVneo was treated with high glucose (HG) to simulate the environment of GDM in vitro. The effects of CTRP9 on the HTR8/SVneo cells and endoplasmic reticulum (ER) stress were analyzed before and after CTRP9 overexpression using reverse transcription‑quantitative PCR and western blotting. The results obtained demonstrated that CTRP9 alleviated ER stress in the trophoblast cell line. After treating with the ER‑stress inducer tunicamycin, cell viability was investigated by performing Cell Counting Kit‑8, TUNEL and western blotting assays, which revealed that CTRP9 increased the activity of HTR8/SVneo cells induced by HG through the alleviation of ER stress. Subsequently, ELISA and western blotting assay results demonstrated that CTRP9 inhibited HG‑induced inflammation of the HTR8/SVneo cells by the reduction in ER stress. Finally, the detection of reactive oxygen species, nitric oxide (NO) synthase and NO levels confirmed that CTRP9 inhibited the oxidative stress of HTR8/SVneo cells induced by HG through the reduction of ER stress. Collectively, the results of the present study suggested that CTRP9 may decrease trophoblast cell damage caused by HG through the suppression of ER stress, and therefore, CTRP9 may potentially be a therapeutic target in the treatment of GDM.

View Figures

View References

1	Coustan DR: Gestational diabetes mellitus. Clin Chem. 59:1310–1321. 2013. View Article : Google Scholar : PubMed/NCBI
2	Laredo-Aguilera JA, Gallardo-Bravo M, Rabanales-Sotos JA, Cobo-Cuenca AI and Carmona-Torres JM: Physical activity programs during pregnancy are effective for the control of gestational diabetes mellitus. Int J Environ Res Public Health. 17:61512020. View Article : Google Scholar : PubMed/NCBI
3	O'Sullivan JB, Gellis SS, Dandrow RV and Tenney BO: The potential diabetic and her treatment in pregnancy. Obstet Gynecol. 27:683–689. 1966.PubMed/NCBI
4	Hill MG and Cohen WR: Shoulder dystocia: Prediction and management. Womens Health (Lond). 12:251–261. 2016. View Article : Google Scholar : PubMed/NCBI
5	Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS and Robinson JS; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group, : Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 352:2477–2486. 2005. View Article : Google Scholar : PubMed/NCBI
6	Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, Wapner RJ, Varner MW, Rouse DJ, Thorp JM Jr, et al: A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 361:1339–1348. 2009. View Article : Google Scholar : PubMed/NCBI
7	Lengyel Z, Boér K, Halászlaki C and Németh Z: Diabetes in patients with malignant tumors. Magy Onkol. 57:177–181. 2013.(In Hu). PubMed/NCBI
8	Rezabakhsh A, Sadeghpour Y, Ghaderi S, Rahbarghazi R and Geranmayeh MH: CTRP9: An emerging potential anti-aging molecule in brain. Cell Signal. 73:1096942020. View Article : Google Scholar : PubMed/NCBI
9	Wu D, Lei H, Wang JY, Zhang CL, Feng H, Fu FY, Li L and Wu LL: CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation. J Mol Med (Berl). 93:1311–1325. 2015. View Article : Google Scholar : PubMed/NCBI
10	Bossi F, Tripodo C, Rizzi L, Bulla R, Agostinis C, Guarnotta C, Munaut C, Baldassarre G, Papa G, Zorzet S, et al: C1q as a unique player in angiogenesis with therapeutic implication in wound healing. Proc Natl Acad Sci USA. 111:4209–4214. 2014. View Article : Google Scholar : PubMed/NCBI
11	Yin C, Ackermann S, Ma Z, Mohanta SK, Zhang C, Li Y, Nietzsche S, Westermann M, Peng L, Hu D, et al: ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med. 25:496–506. 2019. View Article : Google Scholar : PubMed/NCBI
12	Balachandiran M, Bobby Z, Dorairajan G, Gladwin V, Vinayagam V and Packirisamy RM: Decreased maternal serum adiponectin and increased insulin-like growth factor-1 levels along with increased placental glucose transporter-1 expression in gestational diabetes mellitus: Possible role in fetal overgrowth. Placenta. 104:71–80. 2021. View Article : Google Scholar : PubMed/NCBI
13	Sweeting AN, Wong J, Appelblom H, Ross GP, Kouru H, Williams PF, Sairanen M and Hyett JA: A Novel early pregnancy risk prediction model for gestational diabetes mellitus. Fetal Diagn Ther. 45:76–84. 2019. View Article : Google Scholar : PubMed/NCBI
14	Xia L, Zhang H, Shi Q, Zhang X, Wang C and Lin G: Protective role of CTRP3 and CTRP9 in the development of gestational diabetes mellitus. Clin Lab:. 66:2002472020. View Article : Google Scholar
15	Zhao D, Feng P, Sun Y, Qin Z, Zhang Z, Tan Y, Gao E, Lau WB, Ma X, Yang J, et al: Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis. Cell Death Dis. 9:7232018. View Article : Google Scholar : PubMed/NCBI
16	Shen X, Zhang K and Kaufman RJ: The unfolded protein response-a stress signaling pathway of the endoplasmic reticulum. J Chem Neuroanat. 28:79–92. 2004. View Article : Google Scholar : PubMed/NCBI
17	Tabas I and Ron D: Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 13:184–190. 2011. View Article : Google Scholar : PubMed/NCBI
18	Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH and Hotamisligil GS: Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 306:457–461. 2004. View Article : Google Scholar : PubMed/NCBI
19	Liong S and Lappas M: Endoplasmic reticulum stress is increased in adipose tissue of women with gestational diabetes. PLoS One. 10:e01226332015. View Article : Google Scholar : PubMed/NCBI
20	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
21	Alfadhli EM: Gestational diabetes mellitus. Saudi Med J. 36:399–406. 2015. View Article : Google Scholar : PubMed/NCBI
22	Na N and Ji M: Role of first-trimester serum C1q/TNF-related protein 9 in gestational diabetes mellitus. Clin Lab:. 66:2004342020. View Article : Google Scholar
23	Miyatake N, Adachi H, Nomura-Nakayama K, Okada K, Okino K, Hayashi N, Fujimoto K, Furuichi K and Yokoyama H: Circulating CTRP9 correlates with the prevention of aortic calcification in renal allograft recipients. PLoS One. 15:e02265262020. View Article : Google Scholar : PubMed/NCBI
24	Appari M, Breitbart A, Brandes F, Szaroszyk M, Froese N, Korf-Klingebiel M, Mohammadi MM, Grund A, Scharf GM, Wang H, et al: C1q-TNF-related protein-9 promotes cardiac hypertrophy and failure. Circ Res. 120:66–77. 2017. View Article : Google Scholar : PubMed/NCBI
25	Gao C, Zhao S, Lian K, Mi B, Si R, Tan Z, Fu F, Wang S, Wang R, Ma X and Tao L: C1q/TNF-related protein 3 (CTRP3) and 9 (CTRP9) concentrations are decreased in patients with heart failure and are associated with increased morbidity and mortality. BMC Cardiovasc Disord. 19:1392019. View Article : Google Scholar : PubMed/NCBI
26	Bai S, Cheng L, Yang Y, Fan C, Zhao D, Qin Z, Feng X, Zhao L, Ma J, Wang X, et al: C1q/TNF-related protein 9 protects diabetic rat heart against ischemia reperfusion injury: Role of endoplasmic reticulum stress. Oxid Med Cell Longev. 2016:19020252016. View Article : Google Scholar : PubMed/NCBI
27	Jung TW, Park HS, Choi GH, Kim D and Lee T: CTRP9 regulates growth, differentiation, and apoptosis in human keratinocytes through TGFβ1-p38-dependent pathway. Mol Cells. 40:906–915. 2017.PubMed/NCBI
28	Li YX, Run L, Shi T and Zhang YJ: CTRP9 regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and migration via TGF-beta1/ERK1/2 signaling pathway. Biochem Biophys Res Commun. 490:1319–1325. 2017. View Article : Google Scholar : PubMed/NCBI
29	Zuo A, Zhao X, Li T, Li J, Lei S, Chen J, Xu D, Song C, Liu T, Li C and Guo Y: CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway. J Cell Mol Med. 24:2635–2647. 2020. View Article : Google Scholar : PubMed/NCBI
30	Cheng Y, Qi Y, Liu S, Di R, Shi Q, Li J and Pei C: C1q/TNF-related Protein 9 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells through the activation of AMPK/Nrf2 signaling pathway. Cell Transplant. 29:9636897209620522020. View Article : Google Scholar : PubMed/NCBI
31	Zhang L and Zhang S: Modulating Bcl-2 family proteins and caspase-3 in induction of apoptosis by paeoniflorin in human cervical cancer cells. Phytother Res. 25:1551–1557. 2011. View Article : Google Scholar : PubMed/NCBI
32	Duleba AJ and Dokras A: Is PCOS an inflammatory process? Fertil Steril. 97:7–12. 2012. View Article : Google Scholar : PubMed/NCBI
33	Lappas M: Activation of inflammasomes in adipose tissue of women with gestational diabetes. Mol Cell Endocrinol. 382:74–83. 2014. View Article : Google Scholar : PubMed/NCBI
34	Liong S and Lappas M: Endoplasmic reticulum stress regulates inflammation and insulin resistance in skeletal muscle from pregnant women. Mol Cell Endocrinol. 425:11–25. 2016. View Article : Google Scholar : PubMed/NCBI
35	Wu J, Chen S, Liu H, Zhang Z, Ni Z, Chen J, Yang Z, Nie Y and Fan D: Tunicamycin specifically aggravates ER stress and overcomes chemoresistance in multidrug-resistant gastric cancer cells by inhibiting N-glycosylation. J Exp Clin Cancer Res. 37:2722018. View Article : Google Scholar : PubMed/NCBI
36	Brenjian S, Moini A, Yamini N, Kashani L, Faridmojtahedi M, Bahramrezaie M, Khodarahmian M and Amidi F: Resveratrol treatment in patients with polycystic ovary syndrome decreased pro-inflammatory and endoplasmic reticulum stress markers. Am J Reprod Immunol. 83:e131862020. View Article : Google Scholar : PubMed/NCBI
37	Ali SS, Ahsan H, Zia MK, Siddiqui T and Khan FH: Understanding oxidants and antioxidants: Classical team with new players. J Food Biochem. 44:e131452020. View Article : Google Scholar : PubMed/NCBI
38	Zhang P, Li T, Wu X, Nice EC, Huang C and Zhang Y: Oxidative stress and diabetes: Antioxidative strategies. Front Med. 14:583–600. 2020. View Article : Google Scholar : PubMed/NCBI
39	Hu H, Li W, Liu M, Xiong J, Li Y, Wei Y, Huang C and Tang Y: C1q/Tumor necrosis factor-related protein-9 attenuates diabetic nephropathy and kidney fibrosis in db/db mice. DNA Cell Biol. 39:938–948. 2020. View Article : Google Scholar : PubMed/NCBI