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Gadolinium chloride promotes proliferation of HEK293 human embryonic kidney cells by activating EGFR/PI3K/Akt and MAPK pathways

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Abstract

Prolonged exposure to gadolinium-based contrast agents has been reported to trigger nephrogenic systemic fibrosis in end stage renal disease patients. However, the exact molecular mechanisms are not fully understood, and no effective therapy is available to date. In the present study, we report that gadolinium chloride (Gd3+) concentration- and time-dependently promoted the proliferation of HEK293 human embryonic kidney cells by increasing DNA synthesis. Gd3+ treatment increased the protein levels of phosphorylated Akt and MAPKs. Inhibition of Akt and ERK by pharmacological inhibitors abolished the increased proliferation and cell cycle progression. Furthermore, Gd3+ activated EGFR signaling possibly by enhancing EGFR clustering on the cell membrane. Inhibition of EGFR by gefitinib blocked Gd3+-induced proliferation. Gd3+ exposure also upregulated the mRNA levels of TGFβ-1, TGFβR1, TNFα, TIMP-1 and integrin αV, β1 which could also be attenuated by the inhibition of Akt and ERK signaling. Our study provides new clues for the etiological role of Gd3+ in the pathogenesis of nephrogenic systemic fibrosis, and suggests the inhibition of EGFR/Akt/ERK signaling as a potential treatment strategy.

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References

  • Abdel Fattah AR, Mishriki S, Kammann T, Sahu RP, Geng F, Puri IK (2018) Gadopentatic acid affects in vitro proliferation and doxorubicin response in human breast adenocarcinoma cells. Biometals 31:605–616

    Article  CAS  PubMed  Google Scholar 

  • Amet S, Deray G (2012) Renal toxicity of contrast agents in oncologic patients. Bull du Cancer 99:295–307

    Article  CAS  Google Scholar 

  • Barton Pai A, Conner TA, McQuade CR (2009) Therapeutic use of the phosphate binder lanthanum carbonate. Expert Opin Drug Metab Toxicol 5:71–81

    Article  CAS  PubMed  Google Scholar 

  • Ben CS, Slim R, Fathallah N (2015) Fibrosis—a common pathway to organ injury and failure. N Engl J Med 373:95

    Article  Google Scholar 

  • Bernstein EJ, Schmidt-Lauber C, Kay J (2012) Nephrogenic systemic fibrosis: a systemic fibrosing disease resulting from gadolinium exposure. Best Pract Res Clin Rheumatol 26:489–503

    Article  CAS  PubMed  Google Scholar 

  • Bodary SC, McLean JW (1990) The integrin β1 subunit associates with the vitronectin receptor alpha v subunit to form a novel vitronectin receptor in a human embryonic kidney cell line. J Biol Chem 265:5938–5941

    CAS  PubMed  Google Scholar 

  • Chandran S, Petersen J, Jacobs C, Fiorentino D, Doeden K, Lafayette RA (2009) Imatinib in the treatment of nephrogenic systemic fibrosis. Am J Kidney Dis 53:129–132

    Article  PubMed  Google Scholar 

  • Davis RL, Abraham JL (2009) Lanthanum deposition in a dialysis patient. Nephrol Dial Transplant 24:3247–3250

    Article  PubMed  Google Scholar 

  • Edward M, Quinn JA, Mukherjee S, Jensen MB, Jardine AG, Mark PB, Burden AD (2008) Gadodiamide contrast agent ‘activates’ fibroblasts: a possible cause of nephrogenic systemic fibrosis. J Pathol 214:584–593

    Article  CAS  PubMed  Google Scholar 

  • Fu LJ, Li JX, Yang XG, Wang K (2009) Gadolinium-promoted cell cycle progression with enhanced S-phase entry via activation of both ERK and PI3K signaling pathways in NIH 3T3 cells. J Biol Inorg Chem 14:219–227

    Article  CAS  PubMed  Google Scholar 

  • Gao J et al (2015) Mechanistic insights into EGFR membrane clustering revealed by super-resolution imaging. Nanoscale 7:2511–2519

    Article  CAS  PubMed  Google Scholar 

  • Goto K, Ogawa K (2016) Lanthanum deposition is frequently observed in the gastric mucosa of dialysis patients with lanthanum carbonate therapy: a clinicopathologic study of 13 cases, including 1 case of lanthanum granuloma in the colon and 2 nongranulomatous gastric cases. Int J Surg Pathol 24:89–92

    Article  CAS  PubMed  Google Scholar 

  • Grobner T (2006) Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 21:1104–1108

    Article  CAS  PubMed  Google Scholar 

  • Grobner T, Prischl FC (2007) Gadolinium and nephrogenic systemic fibrosis. Kidney Int 72:260–264

    Article  CAS  PubMed  Google Scholar 

  • Hao D, Ai T, Goerner F, Hu X, Runge VM, Tweedle M (2012) MRI contrast agents: basic chemistry and safety. J Magn Reson Imaging 36:1060–1071

    Article  PubMed  Google Scholar 

  • Henderson NC, Sheppard D (2013) Integrin-mediated regulation of TGFbeta in fibrosis. Biochim Biophys Acta 1832:891–896

    Article  CAS  PubMed  Google Scholar 

  • Hu J, Yu S, Yang X, Wang K, Qian Z (2006) Lanthanum induces extracellular signal-regulated kinase phosphorylation through different mechanisms in HeLa cells and NIH 3T3 cells. Biometals 19(1):13–18

    Article  CAS  PubMed  Google Scholar 

  • Idee J-M, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C (2006) Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol 20:563–576

    Article  CAS  PubMed  Google Scholar 

  • Joki N (2009) Pharmacodynamic and pharmacokinetic profile of lanthanum carbonate. Clin Calcium 19:213–218

    CAS  PubMed  Google Scholar 

  • Kelly B, Petitt M, Sanchez R (2008) Nephrogenic systemic fibrosis is associated with transforming growth factor beta and Smad without evidence of renin-angiotensin system involvement. J Am Acad Dermatol 58:1025–1030

    Article  PubMed  Google Scholar 

  • Lacour B, Lucas A, Auchere D, Ruellan N, de Serre Patey NM, Drueke TB (2005) Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration. Kidney Int 67:1062–1069

    Article  CAS  PubMed  Google Scholar 

  • Li JX, Fu LJ, Yang XG, Wang K (2012) Integrin-mediated signaling contributes to gadolinium-containing-particle-promoted cell survival and G1 to S phase cell cycle transition by enhancing focal adhesion formation. J Biol Inorg Chem 17:375–385

    Article  CAS  PubMed  Google Scholar 

  • MacNeil S et al (2011) Gadolinium contrast agent associated stimulation of human fibroblast collagen production. Investig Radiol 46:711–717

    CAS  Google Scholar 

  • Maemondo M et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388

    Article  CAS  Google Scholar 

  • Margadant C, Sonnenberg A (2010) Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep 11:97–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitsumori LM, Bhargava P, Essig M, Maki JH (2014) Magnetic resonance imaging using gadolinium-based contrast agents. Top Magn Reson Imaging 23:51–69

    Article  PubMed  Google Scholar 

  • Morcos SK, Thomsen HS, Webb JA (1999) Contrast-media-induced nephrotoxicity: a consensus report. Contrast media safety committee, european society of urogenital radiology (ESUR). Eur Radiol 9:1602–1613

    Article  CAS  PubMed  Google Scholar 

  • Ramalho J, Semelka RC, Ramalho M, Nunes RH, AlObaidy M, Castillo M (2016) Gadolinium-based contrast agent accumulation and toxicity: an update. Am J Neuroradiol 37:1192–1198

    Article  CAS  PubMed  Google Scholar 

  • Rogosnitzky M, Branch S (2016) Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals 29:365–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanyal S, Marckmann P, Scherer S, Abraham JL (2011) Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis—an autopsy-based review. Nephrol Dial Transplant 26:3616–3626

    Article  CAS  PubMed  Google Scholar 

  • Schmitt-Willich H (2007) Stability of linear and macrocyclic gadolinium based contrast agents. Br J Radiol 80:581–582

    Article  CAS  PubMed  Google Scholar 

  • Shen L, Yang A, Yao P, Sun X, Chen C, Mo C, Shi L, Chen Y, Liu Q (2014) Gadolinium promoted proliferation in mouse embryo fibroblast NIH3T3 cells through Rac and PI3K/Akt signaling pathways. Biometals 27:753–762

    Article  CAS  PubMed  Google Scholar 

  • Staks T, Schuhmann-Giampieri G, Frenzel T, Weinmann HJ, Lange L, Platzek J (1994) Pharmacokinetics, dose proportionality, and tolerability of gadobutrol after single intravenous injection in healthy volunteers. Investig Radiol 29:709–715

    Article  CAS  Google Scholar 

  • Swaminathan S, Arbiser JL, Hiatt KM, High W, Abul-Ezz S, Horn TD, Shah SV (2010) Rapid improvement of nephrogenic systemic fibrosis with rapamycin therapy: possible role of phospho-70-ribosomal-S6 kinase. J Am Acad Dermatol 62:343–345

    Article  CAS  PubMed  Google Scholar 

  • Teo RD, Termini J, Gray HB (2016) Lanthanides: applications in cancer diagnosis and therapy. J Med Chem 59:6012–6024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomsen HS (2004) Gadolinium-based contrast media may be nephrotoxic even at approved doses. Eur Radiol 14:1654–1656

    PubMed  Google Scholar 

  • Yu S, Hu J, Yang X, Wang K, Qian ZM (2006) La(3+)-induced extracellular signal-regulated kinase (ERK) signaling via a metal-sensing mechanism linking proliferation and apoptosis in NIH 3T3 cells. Biochemistry 45:11217–11225

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21001011, 81472657) and the state key laboratory of environmental chemistry and ecotoxicology (KF2013-17). The authors thank the member of Yu’s group for their helpful discussions and suggestions.

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Author notes

  1. Xin Pan and Jinxia Li contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing, 100191, People’s Republic of China

    Xin Pan, Xia He, Kui Wang & Siwang Yu

  2. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences (CAS), Beijing, 100049, People’s Republic of China

    Jinxia Li

  3. Key Lab of Solid Waste Treatment and Resource, Ministry of Education/School of Environment and Resource, Southwest University of Science and Technology, Mianyang, 621010, Sichuan, People’s Republic of China

    Jianjun Deng & Faqin Dong

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  1. Xin Pan
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Correspondence to Siwang Yu.

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Pan, X., Li, J., He, X. et al. Gadolinium chloride promotes proliferation of HEK293 human embryonic kidney cells by activating EGFR/PI3K/Akt and MAPK pathways. Biometals 32, 683–693 (2019). https://doi.org/10.1007/s10534-019-00205-4

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  • DOI: https://doi.org/10.1007/s10534-019-00205-4

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