Skip to main content

Advertisement

SpringerLink
Log in

Alterations in basement membrane immunoreactivity of the diabetic retina in three diabetic mouse models

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

Abstract

Background

The mouse retina contains three kinds of basement membrane (BM) structures; the inner limiting membrane (ILM), Bruch’s membrane (BrM), and the BM surrounding the capillaries. We aimed to investigate possible variations of individual BM components and to detect effects caused by diabetes in three different diabetic mouse models.

Methods

After 4 and 6 months of diabetes (defined by blood glucose > 250 mg/dl), we analyzed by immunohistochemistry the laminin, collagen IV, and nidogen-1 and nidogen-2 protein composition of the BMs obtained from diabetic and non-diabetic Leptin-receptor deficient (db/db) mice and insulin receptor (IR)/insulin receptor substrate-1 (IRS-1) double heterozygous knockout mice. In addition, C57BL/6 J mice were rendered diabetic by intraperitoneal injections of streptozotocin (STZ).

Results

All analyzed BM proteins were detected in all of the three BMs with the exception of collagen IV, which was not detectable in the ILM of db/db mice and IR/IRS-1 mice. We present the first analysis of nidogen expression in diabetic BM. The staining patterns did not differ between the type-1 diabetic model (STZ) or the type-2 diabetic models (db/db and IR/IRS-1) and the wild-type controls, with only one exception: both the db/db mice and the IR/IRS-1 mice but not the STZ mice showed a decreased nidogen-1 immunoreactivity in the BrM after 4 months of diabetes, but not after 6 months.

Conclusions

The BMs in the three mouse strains differ with regard to protein immunoreactivity in the inner limiting membrane. Changes in BM composition may affect both the assembly and the function of the retinal BM. However, there are no marked differences in the BM composition between type-1 and type-2 diabetes. These results provide evidence for BM remodelling during diabetic retinopathy.

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

Similar content being viewed by others

References

  1. Cai J, Boulton M (2002) The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye (Lond) 16:242–260

    Article  CAS  Google Scholar 

  2. Archer DB (1998) External beam radiotherapy in the management of subfoveal choroidal neovascular membranes of the eye: a new treatment for an old disease. Ulst Med J 67(Suppl 1):41–46

    Google Scholar 

  3. Engerman RL, Kern TS (1995) Retinopathy in animal models of diabetes. Diabetes Metab Rev 11:109–120

    Article  PubMed  CAS  Google Scholar 

  4. Feit-Leichman RA, Kinouchi R, Takeda M, Fan Z, Mohr S, Kern TS, Chen DF (2005) Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes. Invest Ophthalmol Vis Sci 46:4281–4287

    Article  PubMed  Google Scholar 

  5. Roy S, Maiello M, Lorenzi M (1994) Increased expression of basement membrane collagen in human diabetic retinopathy. J Clin Invest 93:438–442

    Article  PubMed  CAS  Google Scholar 

  6. Roy S, Sato T, Paryani G, Kao R (2003) Downregulation of fibronectin overexpression reduces basement membrane thickening and vascular lesions in retinas of galactose-fed rats. Diabetes 52:1229–1234

    Article  PubMed  CAS  Google Scholar 

  7. Risteli J, Draeger KE, Regitz G, Neubauer HP (1982) Increase in circulating basement membrane antigens in diabetic rats and effects of insulin treatment. Diabetologia 23:266–269

    Article  PubMed  CAS  Google Scholar 

  8. Brocks DG, Neubauer HP, Strecker H (1985) Type IV collagen antigens in serum of diabetic rats: a marker for basement membrane collagen biosynthesis. Diabetologia 28:928–932

    Article  PubMed  CAS  Google Scholar 

  9. Paulsson M, Timpl R, Brocks DG, Neubauer H (1988) Increased basement membrane heparan sulphate proteoglycan in serum of diabetic rats. Scand J Clin Lab Invest 48:379–380, Letter to Editor article

    Article  CAS  Google Scholar 

  10. Kern JS, Loeckermann S, Fritsch A, Hausser I, Roth W, Magin TM, Mack C, Muller ML, Paul O, Ruther P, Bruckner-Tuderman L (2009) Mechanisms of fibroblast cell therapy for dystrophic epidermolysis bullosa: high stability of collagen VII favors long-term skin integrity. Mol Ther 17:1605–1615

    Article  PubMed  CAS  Google Scholar 

  11. Mayer U, Mann K, Timpl R, Murphy G (1993) Sites of nidogen cleavage by proteases involved in tissue homeostasis and remodelling. Eur J Biochem 217:877–884

    Article  PubMed  CAS  Google Scholar 

  12. Nishikawa T, Giardino I, Edelstein D, Brownlee M (2000) Changes in diabetic retinal matrix protein mRNA levels in a common transgenic mouse strain. Curr Eye Res 21:581–587

    Article  PubMed  CAS  Google Scholar 

  13. Libby RT, Champliaud MF, Claudepierre T, Xu Y, Gibbons EP, Koch M, Burgeson RE, Hunter DD, Brunken WJ (2000) Laminin expression in adult and developing retinae: evidence of two novel CNS laminins. J Neurosci 20:6517–6528

    PubMed  CAS  Google Scholar 

  14. Lin WL, Essner E, McCarthy KJ, Couchman JR (1992) Ultrastructural immunocytochemical localization of chondroitin sulfate proteoglycan in Bruch’s membrane of the rat. Invest Ophthalmol Vis Sci 33:2072–2075

    PubMed  CAS  Google Scholar 

  15. Marshall GE, Konstas AG, Reid GG, Edwards JG, Lee WR (1992) Type IV collagen and laminin in Bruch’s membrane and basal linear deposit in the human macula. Br J Ophthalmol 76:607–614

    Article  PubMed  CAS  Google Scholar 

  16. Grierson I, Hiscott P, Hogg P, Robey H, Mazure A, Larkin G (1994) Development, repair and regeneration of the retinal pigment epithelium. Eye 8(Pt 2):255–262

    Article  PubMed  Google Scholar 

  17. Libby RT, Brunken WJ, Hunter DD (2000) Roles of the extracellular matrix in retinal development and maintenance. Results Probl Cell Differ 31:115–140

    Article  PubMed  CAS  Google Scholar 

  18. Bystrom B, Virtanen I, Rousselle P, Gullberg D, Pedrosa-Domellof F (2006) Distribution of laminins in the developing human eye. Invest Ophthalmol Vis Sci 47:777–785

    Article  PubMed  Google Scholar 

  19. Duran-Jimenez B, Dobler D, Moffatt S, Rabbani N, Streuli CH, Thornalley PJ, Tomlinson DR, Gardiner NJ (2009) Advanced glycation end products in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes. Diabetes 58:2893–2903

    Article  PubMed  CAS  Google Scholar 

  20. Sado Y, Kagawa M, Naito I, Ueki Y, Seki T, Momota R, Oohashi T, Ninomiya Y (1998) Organization and expression of basement membrane collagen IV genes and their roles in human disorders. J Biochem 123:767–776

    Article  PubMed  CAS  Google Scholar 

  21. Chen L, Miyamura N, Ninomiya Y, Handa JT (2003) Distribution of the collagen IV isoforms in human Bruch’s membrane. Br J Ophthalmol 87:212–215

    Article  PubMed  CAS  Google Scholar 

  22. Fox JW, Mayer U, Nischt R, Aumailley M, Reinhardt D, Wiedemann H, Mann K, Timpl R, Krieg T, Engel J et al (1991) Recombinant nidogen consists of three globular domains and mediates binding of laminin to collagen type IV. EMBO J 10:3137–3146

    PubMed  CAS  Google Scholar 

  23. Kimura N, Toyoshima T, Kojima T, Shimane M (1998) Entactin-2: a new member of basement membrane protein with high homology to entactin/nidogen. Exp Cell Res 241:36–45

    Article  PubMed  CAS  Google Scholar 

  24. Miosge N, Holzhausen S, Zelent C, Sprysch P, Herken R (2001) Nidogen-1 and nidogen-2 are found in basement membranes during human embryonic development. Histochem J 33:523–530

    Article  PubMed  CAS  Google Scholar 

  25. Aumailley M, Battaglia C, Mayer U, Reinhardt D, Nischt R, Timpl R, Fox JW (1993) Nidogen mediates the formation of ternary complexes of basement membrane components. Kidney Int 43:7–12

    Article  PubMed  CAS  Google Scholar 

  26. Kohfeldt E, Sasaki T, Gohring W, Timpl R (1998) Nidogen-2: a new basement membrane protein with diverse binding properties. J Mol Biol 282:99–109

    Article  PubMed  CAS  Google Scholar 

  27. Murshed M, Smyth N, Miosge N, Karolat J, Krieg T, Paulsson M, Nischt R (2000) The absence of nidogen 1 does not affect murine basement membrane formation. Mol Cell Biol 20:7007–7012

    Article  PubMed  CAS  Google Scholar 

  28. Schymeinsky J, Nedbal S, Miosge N, Poschl E, Rao C, Beier DR, Skarnes WC, Timpl R, Bader BL (2002) Gene structure and functional analysis of the mouse nidogen-2 gene: nidogen-2 is not essential for basement membrane formation in mice. Mol Cell Biol 22:6820–6830

    Article  PubMed  CAS  Google Scholar 

  29. Bader BL, Smyth N, Nedbal S, Miosge N, Baranowsky A, Mokkapati S, Murshed M, Nischt R (2005) Compound genetic ablation of nidogen 1 and 2 causes basement membrane defects and perinatal lethality in mice. Mol Cell Biol 25:6846–6856

    Article  PubMed  CAS  Google Scholar 

  30. Kunze A, Abari E, Semkova I, Paulsson M, Hartmann U (2010) Deposition of nidogens and other basement membrane proteins in the young and aging mouse retina. Ophthalmic Res 43:108–112

    Article  PubMed  CAS  Google Scholar 

  31. 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

    Article  PubMed  CAS  Google Scholar 

  32. Villarroel M, Ciudin A, Hernandez C, Simo R (2010) Neurodegeneration: An early event of diabetic retinopathy. World J Diabetes 1:57–64

    Article  PubMed  Google Scholar 

  33. King AJ (2012) The use of animal models in diabetes research. Br J Pharmacol 166:877–894

    Article  PubMed  CAS  Google Scholar 

  34. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP (1996) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491–495

    Article  PubMed  CAS  Google Scholar 

  35. Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR (1997) Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88:561–572

    Article  PubMed  CAS  Google Scholar 

  36. McEvoy RC, Andersson J, Sandler S, Hellerstrom C (1984) Multiple low-dose streptozotocin-induced diabetes in the mouse. Evidence for stimulation of a cytotoxic cellular immune response against an insulin-producing beta cell line. J Clin Invest 74:715–722

    Article  PubMed  CAS  Google Scholar 

  37. Stitt AW, Anderson HR, Gardiner TA, Archer DB (1994) Diabetic retinopathy: quantitative variation in capillary basement membrane thickening in arterial or venous environments. Br J Ophthalmol 78:133–137

    Article  PubMed  CAS  Google Scholar 

  38. Bai X, Dilworth DJ, Weng YC, Gould DB (2009) Developmental distribution of collagen IV isoforms and relevance to ocular diseases. Matrix Biol 28:194–201

    Article  PubMed  CAS  Google Scholar 

  39. Smyth N, Vatansever HS, Murray P, Meyer M, Frie C, Paulsson M, Edgar D (1999) Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation. J Cell Biol 144:151–160

    Article  PubMed  CAS  Google Scholar 

  40. Willem M, Miosge N, Halfter W, Smyth N, Jannetti I, Burghart E, Timpl R, Mayer U (2002) Specific ablation of the nidogen-binding site in the laminin gamma1 chain interferes with kidney and lung development. Development 129:2711–2722

    PubMed  CAS  Google Scholar 

  41. Costell M, Carmona R, Gustafsson E, Gonzalez-Iriarte M, Fassler R, Munoz-Chapuli R (2002) Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice. Circ Res 91:158–164

    Article  PubMed  CAS  Google Scholar 

  42. Poschl E, Schlotzer-Schrehardt U, Brachvogel B, Saito K, Ninomiya Y, Mayer U (2004) Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131:1619–1628

    Article  PubMed  Google Scholar 

  43. Pinzon-Duarte G, Daly G, Li YN, Koch M, Brunken WJ (2010) Defective formation of the inner limiting membrane in laminin beta2- and gamma3-null mice produces retinal dysplasia. Invest Ophthalmol Vis Sci 51:1773–1782

    Article  PubMed  Google Scholar 

  44. Hiscott P, Sheridan C, Magee RM, Grierson I (1999) Matrix and the retinal pigment epithelium in proliferative retinal disease. Prog Retin Eye Res 18:167–190

    Article  PubMed  CAS  Google Scholar 

  45. de Gooyer TE, Stevenson KA, Humphries P, Simpson DA, Gardiner TA, Stitt AW (2006) Retinopathy is reduced during experimental diabetes in a mouse model of outer retinal degeneration. Invest Ophthalmol Vis Sci 47:5561–5568

    Article  PubMed  Google Scholar 

  46. Stitt A, Gardiner TA, Alderson NL, Canning P, Frizzell N, Duffy N, Boyle C, Januszewski AS, Chachich M, Baynes JW, Thorpe SR (2002) The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes 51:2826–2832

    Article  PubMed  CAS  Google Scholar 

  47. Oshitari T, Polewski P, Chadda M, Li AF, Sato T, Roy S (2006) Effect of combined antisense oligonucleotides against high-glucose- and diabetes-induced overexpression of extracellular matrix components and increased vascular permeability. Diabetes 55:86–92

    Article  PubMed  CAS  Google Scholar 

  48. Halfter W, Willem M, Mayer U (2005) Basement membrane-dependent survival of retinal ganglion cells. Invest Ophthalmol Vis Sci 46:1000–1009

    Article  PubMed  Google Scholar 

  49. Bai Y, Xu J, Brahimi F, Zhuo Y, Sarunic MV, Saragovi HU (2010) An agonistic TrkB mAb causes sustained TrkB activation, delays RGC death, and protects the retinal structure in optic nerve axotomy and in glaucoma. Invest Ophthalmol Vis Sci 51:4722–4731

    Article  PubMed  Google Scholar 

  50. Martin PM, Roon P, Van Ells TK, Ganapathy V, Smith SB (2004) Death of retinal neurons in streptozotocin-induced diabetic mice. Invest Ophthalmol Vis Sci 45:3330–3336

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Elzbieta Jaroslawska and Peter Knowlton for their help. The study was supported by Deutsche Forschungsgemeinschaft (DFG) PA660/10-1 and JO324/10-1 and by Dr. Werner Jackstädt-Stiftung

Author information

Authors and Affiliations

  1. Ophthalmology, Charité Universitätsmedizin Berlin , Augustenburger Platz 1, 13353, Berlin, Germany

    E. Abari, N. Kociok, I. Semkova & A. M. Joussen

  2. Center for Molecular Medicine (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Disease (CECAD), Center for Biochemistry, University of Cologne, Cologne, Germany

    U. Hartmann & M. Paulsson

  3. Eye Institute, Hong Kong University, Hong Kong, China

    A. Lo

Authors
  1. E. Abari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Kociok
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. U. Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I. Semkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Paulsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. M. Joussen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. Kociok.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abari, E., Kociok, N., Hartmann, U. et al. Alterations in basement membrane immunoreactivity of the diabetic retina in three diabetic mouse models. Graefes Arch Clin Exp Ophthalmol 251, 763–775 (2013). https://doi.org/10.1007/s00417-012-2237-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-012-2237-8

Keywords

Search

Navigation