Skip to main content

Advertisement

SpringerLink
Log in

Up-regulation of integrin-linked kinase in the streptozotocin-induced diabetic rat retina

  • Laboratory Investigation
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Objectives

This study investigated whether integrin-linked kinase (ILK) is involved in the pathogenesis of diabetic retinopathy, by analyzing the expression and activity of ILK in the retina from a streptozotocin (STZ)-induced rat model of diabetes.

Methods

ILK expression in the retina from both control and STZ-induced diabetic rats was measured by reverse transcription polymerase chain reaction, immunohistochemistry and Western blot analysis. The expressions of Akt and FOXO1A, the downstream molecules of ILK, were also examined.

Results

The present study showed that the STZ-induced diabetes was associated with the increase in the vascular permeability in the retina. This elevated vascular permeability increased with the progression of diabetic retinopathy. Meanwhile, the results also showed that the expression of ILK increased in protein and mRNA levels in the retina of STZ-induced diabetic rats. Immunohistochemistry showed that immunostaining of ILK was localized in the outer plexiform layer (OPL), the inner nuclear layer (INL), the inner plexiform layer (IPL), the ganglion cell layer (GCL) and the retinal microvasculature of rats. However, the expression of Akt was reduced in the retinas at 8 and 12 weeks and increased in the retinas at 4 weeks after induction of diabetes. Meanwhile, the expression of the FOXO1A protein increased in the retinas at 8 and 12 weeks and decreased in the retinas at 4 weeks after induction of diabetes. The FOXO1A immunostaining was also observed in the retinal microvasculature and in the OPL, INL, IPL and GCL of rat retinas.

Conclusion

These results indicate that diabetes affects the expression of ILK in the retina. ILK may be involved in the diabetes-induced damage and/or alterations of neural and microvascular structures.

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
Fig. 11

Similar content being viewed by others

References

  1. Yoshida A, Ishiko S, Kojima M, Ogasawara H (1993) Permeability of the blood-ocular barrier in adolescent and adult diabetic patients. Br J Ophthalmol 77:158–161

    PubMed  CAS  Google Scholar 

  2. Schwartz MA, Schaller MD, Ginsberg MH (1995) Integrins: emerging paradigms of signal transduction. Annu Rev Cell Dev Biol 11:549–599

    Article  PubMed  CAS  Google Scholar 

  3. Schlaepfer DD, Hauck CR, Sieg DJ (1999) Signaling through focal adhesion kinase. Prog Biophys Mol Biol 71:435–478

    Article  PubMed  CAS  Google Scholar 

  4. Leu ST, Jacques SA, Wingerd KL, Hikita ST, Tolhurst EC, Pring JL, Wiswell D, Kinney L, Goodman NL, Jackson DY, Clegg DO (2004) Integrin a4β1 function is required for cell survival in developing retina. Dev Biol 276:416–430

    Article  PubMed  CAS  Google Scholar 

  5. Wu C, Dedhar S (2001) Integrin-linked kinase (ILK) and its interactors: a new paradigm for the coupling of extracellular matrix to actin cytoskeletonand signaling complexes. J Cell Biol 155:505–510

    Article  PubMed  CAS  Google Scholar 

  6. Dedhar S (2000) Cell- substrate interactions and signaling through ILK. Curr Opin Cell Biol 12:250–256

    Article  PubMed  CAS  Google Scholar 

  7. Wu C, Keightley SY, Leung-Hagesteijn C, Radeva G, Coppolino M, Goicoechea S, McDonald JA, Dedhar S (1998) Integrin-linked protein kinase regulates fibronectin matrix assembly, E-cadherin expression, and tumorigenicity. J Biol Chem 273:528–536

    Article  PubMed  CAS  Google Scholar 

  8. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S (1998) Phosphoinositide -3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci 95:11211–11216

    Article  PubMed  CAS  Google Scholar 

  9. Brazil DP, Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26:657–664

    Article  PubMed  CAS  Google Scholar 

  10. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241

    Article  PubMed  CAS  Google Scholar 

  11. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321

    Article  PubMed  CAS  Google Scholar 

  12. Plas DR, Talapatra S, Edinger AL, Rathmell JC, Thompson CB (2001) Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J Biol Chem 276:12041–12048

    Article  PubMed  CAS  Google Scholar 

  13. Xu Q, Qaum T, Adamis AP (2001) Sensitive blood-retinal barrier breakdown quantitation using Evans blue. Invest Ophthalmol Vis Sci 42:789–794

    PubMed  CAS  Google Scholar 

  14. Gao G, Shao C, Zhang SX, Dudley A, Fant J, J-x Ma (2003) Kallikrein-binding protein inhibits retinal neovascularization and decreases vascular leakage. Diabetologia 46:689–698

    PubMed  CAS  Google Scholar 

  15. Boeri D, Cagliero E, Podesta F, Lorenzi M (1994) Vascular wall von Willebrand factor in human diabetic retinopathy. Invest Ophthalmol Vis Sci 35:600–607

    PubMed  CAS  Google Scholar 

  16. Legate KR, Montanez E, Kudlacek O, Fassler R (2006) ILK, PINCH and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell Biol 7:20–31

    Article  PubMed  CAS  Google Scholar 

  17. Guo L, Sanders PW, Woods A, Wu C (2001) The distribution and regulation of integrin-linked kinase in normal and diabetic kidneys. Am J Pathol 159:1735–1742

    PubMed  CAS  Google Scholar 

  18. Sakai T, Li S, Docheva D, Grashoff C, Sakai K, Kostka G, Braun A, Pfeifer A, Yurchenco PD, Fassler R (2003) Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation. Genes Dev 17:926–940

    Article  PubMed  CAS  Google Scholar 

  19. Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S (1996) Regulation of cell adhesion and anchorage-dependent growth by a new b1-integrin-linked protein kinase. Nature 379:91–96

    Article  PubMed  CAS  Google Scholar 

  20. Ribatti D (2005) The crucial role of vascular permeability factor/vascular endothelial growth factor in angiogenesis: a historical review. Br J Haematol 128:303–309

    Article  PubMed  CAS  Google Scholar 

  21. Tan C, Mui A, Dedhar S (2002) Integrin-linked kinase regulates inducible nitric oxide synthase and cyclooxygenase-2 expression in an NF-kappa B-dependent manner. J Biol Chem 277:3109–3116

    Article  PubMed  CAS  Google Scholar 

  22. Troussard AA, Costello P, Yoganathan TN, Kumagai S, Roskelley CD, Dedhar S (2000) The Integrin Linked Kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene 19:5444–5452

    Article  PubMed  CAS  Google Scholar 

  23. Das A, Fanslow W, Cerretti D, Warren E, Talarico N, McGuire P (2003) Angiopoietin/Tek interactions regulate MMP-9 expression and retinal neovascularization. Lab Invest 83:8311–1637

    Article  PubMed  CAS  Google Scholar 

  24. Do carmo A, Ramos P, Reis A, Proença R, Cunha-vaz JG (1998) Breakdown of the inner and outer blood retinal barrier in streptozotocin-induced diabetes. Exp Eye Res 67:569–575

    Article  Google Scholar 

  25. Troussard AA, Mawji NN, Ong C, Mui A, St Arnaud R, Dedhar S (2003) Conditional knock-out of integrin-linked kinase (ILK) demonstrates an essential role in PKB/Akt activation. J Biol Chem 278:22374–22378

    Article  PubMed  CAS  Google Scholar 

  26. Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N (2001) Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15:1406–1418

    Article  PubMed  CAS  Google Scholar 

  27. Mizutani M, Kern TS, Lorenzi M (1996) Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 97:2883–2890

    Article  PubMed  CAS  Google Scholar 

  28. Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW (1998) Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 102:783–791

    PubMed  CAS  Google Scholar 

  29. Burgering BM, Kops GJ (2002) Cell cycle and death control long live Forkheads. Trends Biochem Sci 27:352–360

    Article  PubMed  CAS  Google Scholar 

  30. Nickolson KM, Anderson NG (2002) The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14:381–395

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the two anonymous referees whose comments and suggestions greatly helped us to improve the presentation and quality of the paper.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Xijing Hospital, The Fourth Military Medical University and Eye Institute of PLA, Xian, 710032, People’s Republic of China

    Yang-Jun Li, Yan-Nian Hui, Feng Yan & Zhao-Jiang Du

Authors
  1. Yang-Jun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan-Nian Hui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhao-Jiang Du
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yan-Nian Hui.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, YJ., Hui, YN., Yan, F. et al. Up-regulation of integrin-linked kinase in the streptozotocin-induced diabetic rat retina. Graefes Arch Clin Exp Ophthalmol 245, 1523–1532 (2007). https://doi.org/10.1007/s00417-007-0616-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-007-0616-3

Keywords

Search

Navigation