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Tenascin-C promotes the proliferation and fibrosis of mesangial cells in diabetic nephropathy through the β-catenin pathway

  • Nephrology - Review
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Abstract

Objective

To mechanistically assess the involvement of tenascin-C (TNC) in diabetic nephropathy (DN).

Methods

Renal specimens from DN patients were histopathologically examined, and their TNC expression patterns were evaluated via immunohistochemistry. Additionally, the hereditarily diabetic C57BL/KsJ db/db mice were induced to develop DN via adaptive feeding, and then their renal levels of TNC and β-catenin were assessed via western blotting and immunohistochemistry. Furthermore, the TNC and β-catenin levels in primary rat mesangial cells (RMCs) cultured with high glucose levels were assessed via western blotting. In parallel, RMCs cultured with TNC in the presence or absence of the β-catenin blocker ICG-001 were analyzed for their fibronectin and collagen I levels via immunostaining, and for their fibronectin, α-SMA, vimentin, PDGFR-β, PCNA, and β-catenin levels via western blotting.

Results

The TNC levels in the specimens were associated with the pathological classification. In these DN specimens, TNC protein was highly detected in the MCs and slightly in the tubulointerstitium. Renal TNC (P < 0.05) and β-catenin (P < 0.001) were upregulated in db/db vs. db/m mice. High-glucose treatment upregulated TNC (P < 0.01) and β-catenin (P < 0.05) in RMCs. TNC treatment upregulated fibronectin (P < 0.05), α-SMA (P < 0.01), vimentin (P < 0.05), PCNA (P < 0.05), and β-catenin (P < 0.05) in RMCs, as assessed via western blotting. Immunohistochemical analysis confirmed the fibronectin upregulation and showed collagen I upregulation. Western-blot results also showed that levels of fibronectin (P < 0.001), α-SMA (P < 0.01), vimentin (P < 0.001), PCNA (P < 0.05), PDGFR-β (P < 0.05), and β-catenin (P < 0.01) were lower in RMCs co-treated with TNC and ICG-001 than in TNC-treated cells. Immunofluorescence analysis confirmed the decreased fibronectin level and showed that the collagen I level was also decreased by ICG-001.

Conclusion

TNC is upregulated in DN and induces MC proliferation and fibrosis through the β-catenin pathway.

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Data availability

Inquiries for any data unavailable in the text can be directed to the corresponding author.

References

  1. Anders H, Huber T, Isermann B, Schiffer M (2018) CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat Rev Nephrol 14:361–377. https://doi.org/10.1038/s41581-018-0001-y

    Article  CAS  PubMed  Google Scholar 

  2. Tung C, Hsu Y, Shih Y, Chang P, Lin C (2018) Glomerular mesangial cell and podocyte injuries in diabetic nephropathy. Nephrology (Carlton). https://doi.org/10.1111/nep.13451

    Article  PubMed  Google Scholar 

  3. Tucker R, Chiquet-Ehrismann R (2015) Tenascin-C: its functions as an integrin ligand. Int J Biochem Cell Biol 65:165–168. https://doi.org/10.1016/j.biocel.2015.06.003

    Article  CAS  PubMed  Google Scholar 

  4. Fu H, Tian Y, Zhou L, Zhou D, Tan R, Stolz D, Liu Y (2017) Tenascin-C Is a Major Component of the Fibrogenic Niche in Kidney Fibrosis. J Am Soc Nephrol 28:785–801. https://doi.org/10.1681/asn.2016020165

    Article  CAS  PubMed  Google Scholar 

  5. Liabeuf S, Barreto D, Kretschmer A, Barreto F, Renard C, Andrejak M, Massy Z (2011) High circulating levels of large splice variants of tenascin-C is associated with mortality and cardiovascular disease in chronic kidney disease patients. Atherosclerosis 215:116–124. https://doi.org/10.1016/j.atherosclerosis.2010.11.038

    Article  CAS  PubMed  Google Scholar 

  6. Imanaka-Yoshida K, Tawara I, Yoshida T (2020) Tenascin-C in cardiac disease: a sophisticated controller of inflammation, repair, and fibrosis. Am J Physiol Cell Physiol 319:C781–C796. https://doi.org/10.1152/ajpcell.00353.2020

    Article  CAS  PubMed  Google Scholar 

  7. Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, Zhou X, Varga J (2016) Tenascin-C drives persistence of organ fibrosis. Nat Commun 7:11703. https://doi.org/10.1038/ncomms11703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pang X, Zhang Y, Shi X, Li D, Han J (2018) ERp44 depletion exacerbates ER stress and aggravates diabetic nephropathy in db/db mice. Biochem Biophys Res Commun 504:921–926. https://doi.org/10.1016/j.bbrc.2018.09.037

    Article  CAS  PubMed  Google Scholar 

  9. Zhou X, Liu Z, Ying K, Wang H, Liu P, Ji X, He Z (2020) WJ-39, an Aldose Reductase Inhibitor, Ameliorates Renal Lesions in Diabetic Nephropathy by Activating Nrf2 Signaling. Oxid Med Cell Longev 2020:7950457. https://doi.org/10.1155/2020/7950457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen S, Fu H, Wu S, Zhu W, Liao J, Hong X, Liu Y (2019) Tenascin-C protects against acute kidney injury by recruiting Wnt ligands. Kidney Int 95:62–74. https://doi.org/10.1016/j.kint.2018.08.029

    Article  CAS  PubMed  Google Scholar 

  11. Fang X, Hu J, Zhou H (2020) Knock-Down of Long Non-Coding RNA ANRIL Suppresses Mouse Mesangial Cell Proliferation, Fibrosis, Inflammation via Regulating Wnt/β-Catenin and MEK/ERK Pathways in Diabetic Nephropathy. Exp Clin Endocrinol Diabetes.https://doi.org/10.1055/a-1185-9283.

  12. Saupe F, Schwenzer A, Jia Y, Gasser I, Spenlé C, Langlois B, Orend G (2013) Tenascin-C downregulates wnt inhibitor dickkopf-1, promoting tumorigenesis in a neuroendocrine tumor model. Cell Rep 5:482–492. https://doi.org/10.1016/j.celrep.2013.09.014

    Article  CAS  PubMed  Google Scholar 

  13. Hendaoui I, Tucker R, Zingg D, Bichet S, Schittny J, Chiquet-Ehrismann R (2014) Tenascin-C is required for normal Wnt/β-catenin signaling in the whisker follicle stem cell niche. Matrix Biol 40:46–53. https://doi.org/10.1016/j.matbio.2014.08.017

    Article  CAS  PubMed  Google Scholar 

  14. Xu W, Guan M, Zheng Z, Gao F, Zeng Y, Qin Y, Xue Y (2014) Exendin-4 alleviates high glucose-induced rat mesangial cell dysfunction through the AMPK pathway. Cell Physiol Biochem 33:423–432. https://doi.org/10.1159/000358623

    Article  CAS  PubMed  Google Scholar 

  15. Cai M, Bompada P, Atac D, Laakso M, Groop L, De Marinis Y (2016) Epigenetic regulation of glucose-stimulated osteopontin (OPN) expression in diabetic kidney. Biochem Biophys Res Commun 469:108–113. https://doi.org/10.1016/j.bbrc.2015.11.079

    Article  CAS  PubMed  Google Scholar 

  16. Tervaert T, Mooyaart A, Amann K, Cohen A, Cook H, Drachenberg C, Bruijn J (2010) Pathologic classification of diabetic nephropathy. J Am Soc Nephrol 21:556–563. https://doi.org/10.1681/asn.2010010010

    Article  PubMed  Google Scholar 

  17. Wang J, Yang Q, Nie Y, Guo H, Zhang F, Zhou X, Yin X (2017) Tetrahydrobiopterin contributes to the proliferation of mesangial cells and accumulation of extracellular matrix in early-stage diabetic nephropathy. J Pharm Pharmacol 69:182–190. https://doi.org/10.1111/jphp.12677

    Article  CAS  PubMed  Google Scholar 

  18. Zou C, Xie R, Bao Y, Liu X, Sui M, Suhong M, Li S, Yin H (2013) Iron chelator alleviates tubulointerstitial fibrosis in diabetic nephropathy rats by inhibiting the expression of tenascinC and other correlation factors. Endocrine 44:666–674. https://doi.org/10.1007/s12020-013-9907-0

    Article  CAS  PubMed  Google Scholar 

  19. He W, Dai C, Li Y, Zeng G, Monga S, Liu Y (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol 20:765–776. https://doi.org/10.1681/asn.2008060566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shi M, Tian P, Liu Z, Zhang F, Zhang Y, Qu L, Guo B (2020) MicroRNA-27a targets Sfrp1 to induce renal fibrosis in diabetic nephropathy by activating Wnt/β-Catenin signalling. Biosci Rep. https://doi.org/10.1042/bsr20192794

  21. Shimojo N, Hashizume R, Kanayama K, Hara M, Suzuki Y, Nishioka T, Imanaka-Yoshida K (2015) Tenascin-C may accelerate cardiac fibrosis by activating macrophages via the integrin αVβ3/nuclear factor-κB/interleukin-6 axis. Hypertension 66:757–766. https://doi.org/10.1161/hypertensionaha.115.06004

    Article  CAS  PubMed  Google Scholar 

  22. Ishigaki T, Imanaka-Yoshida K, Shimojo N, Matsushima S, Taki W, Yoshida T (2011) Tenascin-C enhances crosstalk signaling of integrin αvβ3/PDGFR-β complex by SRC recruitment promoting PDGF-induced proliferation and migration in smooth muscle cells. J Cell Physiol 226:2617–2624. https://doi.org/10.1002/jcp.22614

    Article  CAS  PubMed  Google Scholar 

  23. Buelli S, Rosanò L, Gagliardini E, Corna D, Longaretti L, Pezzotta A, Benigni A (2014) β-arrestin-1 drives endothelin-1-mediated podocyte activation and sustains renal injury. J Am Soc Nephrol 25:523–533. https://doi.org/10.1681/asn.2013040362

    Article  CAS  PubMed  Google Scholar 

  24. Ridgway R, Serrels B, Mason S, Kinnaird A, Muir M, Patel H, Brunton V (2012) Focal adhesion kinase is required for β-catenin-induced mobilization of epidermal stem cells. Carcinogenesis 33:2369–2376. https://doi.org/10.1093/carcin/bgs284

    Article  CAS  PubMed  Google Scholar 

  25. Despeaux M, Chicanne G, Rouer E, De Toni-Costes F, Bertrand J, Mansat-De Mas V, Racaud-Sultan C (2012) Focal adhesion kinase splice variants maintain primitive acute myeloid leukemia cells through altered Wnt signaling. Stem Cells 30:1597–1610. https://doi.org/10.1002/stem.1157

    Article  CAS  PubMed  Google Scholar 

  26. Malanchi I, Santamaria-Martínez A, Susanto E, Peng H, Lehr H, Delaloye J, Huelsken J (2011) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481:85–89. https://doi.org/10.1038/nature10694

    Article  CAS  PubMed  Google Scholar 

  27. Lan X, Wen H, Aslam R, Shoshtari S, Mishra A, Kumar V, Singhal P (2018) Nicotine enhances mesangial cell proliferation and fibronectin production in high glucose milieu via activation of Wnt/β-catenin pathway. Biosci Rep. https://doi.org/10.1042/bsr20180100

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Acknowledgements

Our thanks go to all laboratory members who helped to carry out this project.

Funding

This work was supported by the National Natural Science Foundation of China Grant 81900627, Guangxi Natural Science Foundation grant 2021GXNSFAA196057, Guangxi Administration of Traditional Chinese Medicine grant GZZC2019107 and Guangxi Science and Technology Base and Talent Project grant 2022AC04001.

Author information

Author notes

  1. Xinxin Pang and Xiaotao Hou contributed equally to this work.

Authors and Affiliations

  1. Division of Nephrology, Henan Provincial Hospital of Traditional Chinese Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, China

    Xinxin Pang

  2. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Xiaotao Hou & Jun Zhou

  3. Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Xiaotao Hou & Jun Zhou

  4. Department of Renal Pathology, King Medical Diagnostics Center, Guangzhou, China

    Xiaotao Hou

  5. Division of Nephrology, Shenzhen Hospital, Hong Kong University, Shenzhen, China

    Chengxiao Hu

  6. Division of Nephrology, Ruikang Hospital, Guangxi University of Traditional Chinese Medicine, Guangxi Integrated Chinese and Western Medicine Clinical Research Center for Kidney Disease, Nanning, 530000, China

    Shilong Lu, Huifang Gan, Shaowei Xiang & Shuangqin Chen

  7. Fuda Cancer Hospital, Jinan University, Guangzhou, China

    Huifei Yang

  8. Division of Urology, Ruikang Hospital, Guangxi University of Traditional Chinese Medicine, Guangxi Integrated Chinese and Western Medicine Clinical Research Center for Kidney Disease, Nanning, 530000, China

    Hongjun Gao

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Contributions

H-XT, H-CH, L-SL, G-HF, X-SW, Y-HF, Z-J, C-SQ, and G-HJ designed and performed the experiments, and collected and analyzed the data. C-SQ helped in performing the experiments and collecting the data. P-XX and C-SQ wrote the manuscript draft. C-SQ analyzed the data and prepared the figures. G-HJ finished the final touch-up of the article. All the authors contributed to the article and approved the submitted version.111.

Corresponding authors

Correspondence to Hongjun Gao or Shuangqin Chen.

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Pang, X., Hou, X., Hu, C. et al. Tenascin-C promotes the proliferation and fibrosis of mesangial cells in diabetic nephropathy through the β-catenin pathway. Int Urol Nephrol 55, 2507–2516 (2023). https://doi.org/10.1007/s11255-023-03547-8

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