Skip to main content
SpringerLink
Log in

Response of VEGF to activation of viral receptors and TNFα in human mesangial cells

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

Abstract

Vascular endothelial growth factor (VEGF) plays an important role in glomerular homeostasis as well as in the pathogenesis of kidney diseases as glomerulonephritis (GN) and diabetic nephropathy. Mesangial cells (MC), which are an integral part of the functional glomerular filtration barrier in that providing structural support, can behave like inflammatory cells and produce mediators as chemokines and growth factors; they are known to express viral receptors, with TLR3 having been attributed relevance in viral disease-associated GN. Experiments were performed on human MC in cell culture. Stimulation experiments were performed with poly (I:C) and hepatitis C RNA from patients with hepatitis C infection. We hereby show a TLR3-mediated upregulation of VEGF and its receptor subtype 2 (VEGF-R2) in human MC upon activation of viral receptors by poly (I:C) and hepatitis C virus. The increase in VEGF expression levels is further enhanced by tumor necrosis factor alpha (TNFα) which also induces the cytokines IL-6 and IL-8 as well as the chemokines MCP-1 and RANTES. These effects are potentiated by preincubation of MC with poly (I:C), just as the induction of the viral receptors TLR3, RIG-1, and MDA5 themselves. Moreover, MCP-1 itself is able to significantly increase mesangial VEGF expression. Therefore, with VEGF and VEGF-R2 being induced upon viral receptor activation in human MC, a novel role of TLR3 in mediating glomerular damage in virally induced or aggravated GN is inferred. TNFα and MCP-1 are seemingly important in amplifying VEGF effects in the setting of virally induced inflammation, with TNFα being also able to induce other mediators of glomerular pathology in GN.

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

Similar content being viewed by others

References

  1. Ziyadeh FN, Wolf G (2008) Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 4:39–45

    Article  PubMed  CAS  Google Scholar 

  2. LeHir M, Kriz W (2007) New insights into structural patterns encountered in glomerulosclerosis. Curr Opin Nephrol Hypertens 16:184–191

    Article  PubMed  Google Scholar 

  3. Nitta K, Uchida K, Kimata N, Honda K, Horita S, Hayashi T, Ishizuka T, Kobayashi H, Kawashima A, Yumura W, Nihei H (1999) Increased serum levels of vascular endothelial growth factor in human crescentic glomerulonephritis. Clin Nephrol 52:76–82

    PubMed  CAS  Google Scholar 

  4. Navarro C, Candia-Zúñiga L, Silveira LH, Ruiz V, Gaxiola M, Avila MC, Amigo MC (2002) Vascular endothelial growth factor plasma levels in patients with systemic lupus erythematosus and primary antiphospholipid syndrome. Lupus 11:21–24

    Article  PubMed  CAS  Google Scholar 

  5. Haas CS, Câmpean V, Kuhlmann A, Dimmler A, Reulbach U, Forster C, Aigner T, Acker T, Plate K, Amann K (2007) Analysis of glomerular VEGF mRNA and protein expression in murine mesangioproliferative glomerulonephritis. Virchows Arch 450:81–92

    Article  PubMed  CAS  Google Scholar 

  6. Kunter U, Rong S, Djuric Z, Boor P, Müller-Newen G, Yu D, Floege J (2006) Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis. J Am Soc Nephrol 17:2202–2212

    Article  PubMed  CAS  Google Scholar 

  7. Masuda Y, Shimizu A, Kataoka M, Arai T, Ishikawa A, Du X, Saito SK, Aki K, Nagasaka S, Mii A, Fujita E, Fukuda Y (2010) Inhibition of capillary repair in proliferative glomerulonephritis results in persistent glomerular inflammation with glomerular sclerosis. Lab Investig 90:1468–1481

    Article  PubMed  CAS  Google Scholar 

  8. Avihingsanon Y, Benjachat T, Tassanarong A, Sodsai P, Kittikovit V, Hirankarn N (2009) Decreased renal expression of vascular endothelial growth factor in lupus nephritis is associated with worse prognosis. Kidney Int 75:1340–1348

    Article  PubMed  CAS  Google Scholar 

  9. Hakroush S, Moeller MJ, Theilig F, Kaissling B, Sijmonsma TP, Jugold M, Akeson AL, Traykova-Brauch M, Hosser H, Hähnel B, Gröne HJ, Koesters R, Kriz W (2009) Effects of increased renal tubular vascular endothelial growth factor (VEGF) on fibrosis, cyst formation, and glomerular disease. Am J Pathol 175:1883–1895

    Article  PubMed  CAS  Google Scholar 

  10. Thomas S, Vanuystel J, Gruden G, Rodríguez V, Burt D, Gnudi L, Hartley B, Viberti G (2000) Vascular endothelial growth factor receptors in human mesangium in vitro and in glomerular disease. J Am Soc Nephrol 11:1236–1243

    PubMed  CAS  Google Scholar 

  11. Hohenstein B, Colin M, Foellmer C, Amann KU, Brekken RA, Daniel C, Hugo CP (2010) Autocrine VEGF–VEGF-R loop on podocytes during glomerulonephritis in humans. Nephrol Dial Transplant 25:3170–3180

    Article  PubMed  CAS  Google Scholar 

  12. Wörnle M, Schmid H, Banas B, Merkle M, Henger A, Roeder M, Blattner S, Bock E, Kretzler M, Gröne HJ, Schlöndorff D (2006) Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis. Am J Pathol 168:370–385

    Article  PubMed  Google Scholar 

  13. Wörnle M, Roeder M, Sauter M, Ribeiro A (2009) Role of matrix metalloproteinases in viral-associated glomerulonephritis. Nephrol Dial Transplant 24:1113–1121

    Article  PubMed  Google Scholar 

  14. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-κB by toll-like receptor 3. Nature 413:732–738

    Article  PubMed  CAS  Google Scholar 

  15. Hassan M, Selimovic D, Ghozlan H, Abdel-kader O (2009) Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways. Hepatology 49:1469–1482

    Article  PubMed  CAS  Google Scholar 

  16. Mee CJ, Farquhar MJ, Harris HJ, Hu K, Ramma W, Ahmed A, Maurel P, Bicknell R, Balfe P, McKeating JA (2010) Hepatitis C virus infection reduces hepatocellular polarity in a vascular endothelial growth factor-dependent manner. Gastroenterology 138:1134–1142

    Article  PubMed  CAS  Google Scholar 

  17. Banas B, Wörnle M, Berger T, Nelson PJ, Cohen CD, Kretzler M, Pfirstinger J, Mack M, Lipp M, Gröne HJ, Schlöndorff D (2002) Roles of SLC/CCL21 and CCR7 in human kidney for mesangial proliferation, migration, apoptosis, and tissue homeostasis. J Immunol 168:4301–4307

    PubMed  CAS  Google Scholar 

  18. Matsukura S, Kokubu F, Kurokawa M, Kawaguchi M, Ieki K, Kuga H, Odaka M, Suzuki S, Watanabe S, Homma T, Takeuchi H, Nohtomi K, Adachi M (2007) Role of RIG-I, MDA-5, and PKR on the expression of inflammatory chemokines induced by synthetic dsRNA in airway epithelial cells. Int Arch Allergy Immunol 143(Suppl 1):80–83

    Article  PubMed  CAS  Google Scholar 

  19. Masciopinto F, Giovani C, Campagnoli S, Galli-Stampino L, Colombatto P, Brunetto M, Yen TS, Houghton M, Pileri P, Abrignani S (2004) Association of hepatitis C virus envelope proteins with exosomes. Eur J Immunol 34:2834–2842

    Article  PubMed  CAS  Google Scholar 

  20. Ye L, Wang X, Wang S, Luo G, Wang Y, Liang H, Ho W (2008) Centrifugal enhancement of hepatitis C virus infection of human hepatocytes. J Virol Methods 148:161–165

    Article  PubMed  CAS  Google Scholar 

  21. Merkle M, Ribeiro A, Wörnle M (2011) TLR3 dependent regulation of cytokines in human mesangial cells: a novel role for IP-10 and TNFα in hepatitis C associated glomerulonephritis. Am J Physiol Ren Physiol 301:57–69

    Article  Google Scholar 

  22. Liu E, Morimoto M, Kitajima S, Koike T, Yu Y, Shiiki H, Nagata M, Watanabe T, Fan J (2007) Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions. J Am Soc Nephrol 18:2094–2104

    Article  PubMed  CAS  Google Scholar 

  23. Eremina V, Cui Eremina V, Cui S, Gerber H, Ferrara N, Haigh J, Nagy A, Ema M, Rossant J, Jothy S, Miner JH, Quaggin SE (2006) Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol 17:724–735

    Article  PubMed  CAS  Google Scholar 

  24. Shibuya M (2006) Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol 39:469–478

    Article  PubMed  CAS  Google Scholar 

  25. Niu J, Azfer A, Zhelyabovska O, Fatma S, Kolattukudy PE (2008) Monocyte chemotactic protein (MCP)-1 promotes angiogenesis via a novel transcription factor, MCP-1-induced protein (MCPIP). J Biol Chem 283:14542–14551

    Article  PubMed  CAS  Google Scholar 

  26. Varney ML, Olsen KJ, Mosley RL, Singh RK (2005) Paracrine regulation of vascular endothelial growth factor—a expression during macrophage-melanoma cell interaction: role of monocyte chemotactic protein-1 and macrophage colony-stimulating factor. J Interferon Cytokine Res 25:674–683

    Article  PubMed  CAS  Google Scholar 

  27. Yamagishi S, Inagaki Y, Okamoto T, Amano S, Koga K, Takeuchi M, Makita Z (2002) Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. J Biol Chem 77:20309–20315

    Article  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Else Kröner-Fresenius-Stiftung, the Wilhelm-Vaillant-Stiftung and the Fritz Bender Stiftung to M.W.

Author information

Authors and Affiliations

  1. Medizinische Klinik und Poliklinik IV, Klinikum der LMU, Ziemssenstrasse 1, 80336, Munich, Germany

    Monika Merkle, Andrea Ribeiro, Franziska Belling, Hanna Mannell, Florian Krötz, Joachim Pircher & Markus Wörnle

Authors
  1. Monika Merkle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Franziska Belling
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanna Mannell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Florian Krötz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joachim Pircher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Markus Wörnle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus Wörnle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Merkle, M., Ribeiro, A., Belling, F. et al. Response of VEGF to activation of viral receptors and TNFα in human mesangial cells. Mol Cell Biochem 370, 151–161 (2012). https://doi.org/10.1007/s11010-012-1406-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-012-1406-8

Keywords

Search

Navigation