Skip to main content

Advertisement

SpringerLink
Log in

Role of the ER stress in prostaglandin E2/E-prostanoid 2 receptor involved TGF-β1-induced mice mesangial cell injury

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

This study aims to investigate the relationship between prostaglandin E2 E-prostanoid 2 receptor (EP2) and Endoplasmic reticulum (ER) stress in transforming growth factor-β1 (TGF-β1)-induced mouse glomerular mesangial cells (MCs) injury. We cultured primary WT, EP2−/− MCs (EP2 deleted), and adenovirus-EP2-infected WT MCs (EP2 overexpressed). PCR, Western blot, flow cytometry, and immunohistochemical technique were used in in vitro and in vivo experiments. We found that TGF-β1-induced PGE2 synthesis decreased in EP2-deleted MCs and increased in EP2-overexpressed MCs. EP2 deficiency in these MCs augmented the coupling of TGF-β1 to ER stress-associated proteins [chaperone glucose-regulated protein 78 (GRP78), transient receptor potential channel 1 (TRPC1), and transient receptor potential channel 4 (TRPC4)], and upregulation of EP2 showed no significant change of GRP78, but augmented the expression of TRPC1, while TRPC4 expression was downregulated in comparison to normal MCs. In addition, EP2 deficiency in MCs augmented TGF-β1-induced fibronectin (FN), cyclooxygenase-2 (COX2), and CyclinD1 expression. Silencing of EP2 also strengthened TGF-β1-induced extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Flow Cytometry showed that silencing of EP2 significantly promoted the apoptosis of MCs. In contrast, EP2 overexpression reversed the effects of EP2 deficiency. 8 weeks after 5/6 nephrectomy (Nx), blood urea nitrogen and creatinine concentrations were significantly increased in EP2−/− 5/6Nx mice as compared to those of WT 5/6Nx mice. The pathological changes in kidney of EP2−/− mice were markedly aggravated compared with WT mice. Immunohistochemical analysis showed significant augment of TRPC4 and ORP150 in the kidney of EP2−/− mice compared with WT mice. Considering all the findings, it is suggested that increased expression of EP2 may prevent TGF-β1-induced MCs damage through ER stress regulatory pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Oujo B, Muñoz-Félix JM, Arévalo M, Núñez-Gómez E, Pérez-Roque L, Pericacho M, González-Núñez M, Langa C, Martínez-Salgado C, Perez-Barriocanal F, Bernabeu C, Lopez-Novoa JM (2014) L-Endoglin overexpression increases renal fibrosis after unilateral ureteral obstruction. PLoS ONE 9:e110365

    Article  PubMed Central  PubMed  Google Scholar 

  2. Chen GT, Zhang L, Liao XH, Yan RY, Li Y, Sun H, Guo H, Liu Q (2014) Augmenter of liver regeneration ameliorates renal fibrosis in rats with obstructive nephropathy. Biosci Rep 34:e00135

    PubMed Central  PubMed  Google Scholar 

  3. Border WA, Okuda S, Languino LR, Ruoslahti E (1990) Transforming growth factor-beta regulates production of proteoglycans by mesangial cells. Kidney Int 37:689–695

    Article  CAS  PubMed  Google Scholar 

  4. Bitzer M, Sterzel RB, Bottinger EP (1998) Transforming growth factor-beta in renal disease. Kidney Blood Press Res 21:1–12

    Article  CAS  PubMed  Google Scholar 

  5. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  CAS  PubMed  Google Scholar 

  6. Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18:716–731

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Malhotra JD, Miao H, Zhang K, Wolfson A, Pennathur S, Pipe SW, Kaufman RJ (2008) Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc Natl Acad Sci USA 105:18525–18530

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134:743–756

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Inagi R (2010) Endoplasmic reticulum stress as a progression factor for kidney injury. Curr Opin Pharmacol 10:156–165

    Article  CAS  PubMed  Google Scholar 

  10. Ohse T, Inagi R, Tanaka T, Ota T, Miyata T, Kojima I, Ingelfinger JR, Ogawa S, Fujita T, Nangaku M (2006) Albumin induces endoplasmic reticulum stress and apoptosis in renal proximal tubular cells. Kidney Int 70:1447–1455

    Article  CAS  PubMed  Google Scholar 

  11. Mu YP, Ogawa T, Kawada N (2010) Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methioninecholine-deficient diet. Lab Invest 90:245–256

    Article  CAS  PubMed  Google Scholar 

  12. Tamaki N, Hatano E, Taura K, Tada M, Kodama Y, Nitta T, Iwaisako K, Seo S, Nakajima A, Ikai I, Uemoto S (2008) CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol 294:G498–505

    Article  CAS  PubMed  Google Scholar 

  13. Dickhout JG, Carlisle RE, Austin RC (2011) Interrelationship between cardiac hypertrophy, heart failure, and chronic kidney disease endoplasmic reticulum stress as a mediator of pathogenesis. Circ Res 108:629–642

    Article  CAS  PubMed  Google Scholar 

  14. Dihazi H, Dihazi GH, Mueller C, Lahrichi L, Asif AR, Bibi A, Eltoweissy M, Vasko R, Mueller GA (2011) Proteomics characterization of cell model with renal fibrosis phenotype: osmotic stress as fibrosis triggering factor. J Proteom 74:304–318

    Article  CAS  Google Scholar 

  15. Breyer RM, Bagdassarian CK, Myers SA, Breyer MD (2001) Prostanoid receptors: subtypes and signaling. Annu Rev Pharmacol Toxicol 41:661–690

    Article  CAS  PubMed  Google Scholar 

  16. Li NN, Xu YY, Chen XL, Fan YP, Wu JH (2014) Role of the prostaglandin E2/E-prostanoid 2 receptor signalling pathway in TGFβ-induced mice mesangial cell damage. Biosci Rep 34:e00159

    PubMed Central  PubMed  Google Scholar 

  17. Yang GX, Xu YY, Fan YP, Wang J, Chen XL, Zhang YD, Wu JH (2014) A maladaptive role for EP4 receptors in mouse mesangial cells. PLoS ONE 9:e104091

    Article  PubMed Central  PubMed  Google Scholar 

  18. Sugimoto Y, Narumiya S (2007) Prostaglandin E receptors. J Biol Chem 282:11613–11617

    Article  CAS  PubMed  Google Scholar 

  19. Kennedy CR, Zhang Y, Brandon S, Guan Y, Coffee K, Funk CD, Magnuson MA, Oates JA, Breyer MD, Breyer RM (1999) Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nat Med 5:217–220

    Article  CAS  PubMed  Google Scholar 

  20. Wadleigh DJ, Reddy ST, Kopp E, Ghosh S, Herschman HR (2000) Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. J Biol Chem 275:6259–6266

    Article  CAS  PubMed  Google Scholar 

  21. Huang CZ, Huang WZ, Zhang G, Tang DL (2013) In vivo study on the effects of curcumin on the expression profiles of anti-tumour genes (VEGF, CyclinD1 and CDK4) in liver of rats injected with DEN. Mol Biol Rep 40:5825–5831

    Article  CAS  PubMed  Google Scholar 

  22. Srivastava V, Patel B, Kumar M, Shukla M, Pandey M (2013) Cyclin D1, retinoblastoma and p16 protein expression in carcinoma of the gallbladder. Asian Pac J Cancer Prev 14:2711–2715

    Article  PubMed  Google Scholar 

  23. Xiong CJ, Li PF, Song YL, Xue LX, Jia ZQ, Yao CX, Wei QX, Zhang SF, Zhang SF, Zhang YY, Zhao JM, Wang TQ, Guo MF, Zang MX (2013) Insulin induces C2C12 cell proliferation and apoptosis through regulation of cyclin D1 and BAD expression. J Cell Biochem 114:2708–2717

    Article  CAS  PubMed  Google Scholar 

  24. Kolodsick JE, Peters-Golden M, Larios J, Toews GB, Thannickal VJ, Moore BB (2003) Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. Prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation. Am J Respir Cell Mol Biol 29:537–544

    Article  CAS  PubMed  Google Scholar 

  25. Cybulsky AV (2010) Endoplasmic reticulum stress in proteinuric kidney disease. Kidney Int 77:187–193

    Article  CAS  PubMed  Google Scholar 

  26. Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S, Hirata A, Fujita M, Nagamachi Y, Nakatani T, Yutani C, Ozawa K, Ogawa S, Tomoike H, Hori M, Kitakaze M (2004) Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110:705–712

    Article  PubMed  Google Scholar 

  27. Peyrou M, Hanna PE, Cribb AE (2004) Cisplatin, gentamicin, and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys. Toxicol Sci 99:346–353

    Article  Google Scholar 

  28. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307:935–939

    Article  CAS  PubMed  Google Scholar 

  29. Kim TW, Michniewicz M, Bergmann DC, Wang ZY (2012) Brassinosteroid regulates stomatal development by GSK3-mediated inhibition of a MAPK pathway. Nature 482:419–422

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Sayama K, Hanakawa Y, Nagai H, Shirakata Y, Dai X, Hirakawa S, Tokumaru S, Tohyama M, Yang L, Sato S, Shizuo A, Hashimoto K (2006) Transforming growth factor-β-activated kinase 1 is essential for differentiation and the prevention of apoptosis in epidermis. J Biol Chem 281:22013–22020

    Article  CAS  PubMed  Google Scholar 

  31. Lu Y, Yang JH, Li X, Hwangbo K, Hwang SL, Taketomi Y, Murakami M, Chang YC, Kim CH, Son JK, Chang HW (2011) Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell activation. Biochem Pharmacol 82:1700–1708

    Article  CAS  PubMed  Google Scholar 

  32. Xie YQ, Wu XB, Tang SQ (2014) Curcumin treatment alters ERK 1/2 signaling in vitro and inhibits nasopharyngeal carcinoma proliferation in mouse xenografts. Int J Clin Exp Med 7:108–114

    PubMed Central  PubMed  Google Scholar 

  33. Kawakami T, Inagi R, Wada T, Tanaka T, Fujita T, Nangaku M (2010) Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress. Am J Physiol Renal Physiol 299:F568–F576

    Article  CAS  PubMed  Google Scholar 

  34. Gao Z, Liu G, Hu Z, Li X, Yang X, Jiang B, Li X (2014) Grape seed proanthocyanidin extract protects from cisplatin-induced nephrotoxicity by inhibiting endoplasmic reticulum stress-induced apoptosis. Mol Med Rep 9:801–807

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by fundings from the National Natural Science Foundation of China (No.81170656), Jiangsu Basic Research Program (BK2008185), and the Science Foundation of Nantong City, Jiangsu province, China (N1o. HS2011021).

Author information

Authors and Affiliations

  1. Department of Nephrology, Affiliated Hospital of Nantong university, Nantong, Jiangsu, China

    Yuyin Xu, Tianyi Pan, Xiaolan Chen, Xiaolin Xu, Daishan Jiang & Jun Yin

  2. Shanghai Jiaotong University, School of Medicine, Shanghai, China

    Jing Wang

Authors
  1. Yuyin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tianyi Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaolan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaolin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daishan Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaolan Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Yuyin Xu and Jing Wang are joint first authors of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, Y., Wang, J., Pan, T. et al. Role of the ER stress in prostaglandin E2/E-prostanoid 2 receptor involved TGF-β1-induced mice mesangial cell injury. Mol Cell Biochem 411, 43–55 (2016). https://doi.org/10.1007/s11010-015-2567-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-015-2567-z

Keywords

Search

Navigation