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Impact of diabetes on alpha-crystallins and other heat shock proteins in the eye

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Journal of Ocular Biology, Diseases, and Informatics

Abstract

Diabetes and its related complications represent a major growing health concern and economic burden worldwide. Ocular manifestations of diabetes include cataractogenesis and retinopathy, the latter being the leading cause of blindness in the working-age population. Despite numerous studies and recent progress, the exact pathophysiology of the disease remains to be fully elucidated and development of new and improved therapeutic strategies for this chronic condition are greatly needed. Heat shock proteins (Hsps) are highly conserved families of proteins, which are generally regarded as protective molecules that play a wide variety of roles and can be expressed in response to different types of cellular stresses. In recent years, numerous studies have reported their implication in various ocular diseases including diabetic retinopathy. The present review focuses on the potential implication of Hsps in ocular diabetic complications and discusses their specific mechanisms of regulation with respect to their expression, functions and alteration during diabetes. The review will conclude by examining the potential of Hsps as therapeutic agents or targets for the treatment of diabetic retinopathy.

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References

  1. Lindquist S, Craig EA. The heat-shock proteins. Annu Rev Genet. 1988;22:631–77.

    Article  PubMed  CAS  Google Scholar 

  2. Csermely P. A nonconventional role of molecular chaperones: involvement in the cytoarchitecture. News Physiol Sci. 2001;16:123–6.

    PubMed  CAS  Google Scholar 

  3. O'Reilly AM, Currie RW, Clarke DB. HspB1 (Hsp 27) expression and neuroprotection in the retina. Mol Neurobiol. 2010;42(2):124–32.

    Article  PubMed  Google Scholar 

  4. Kojima M, et al. Expression of heat shock proteins in the developing rat retina. Neurosci Lett. 1996;205(3):215–7.

    Article  PubMed  CAS  Google Scholar 

  5. Hawkes EL, et al. Expression of Hsp27 in retinal ganglion cells of the rat during postnatal development. J Comp Neurol. 2004;478(2):143–8.

    Article  PubMed  CAS  Google Scholar 

  6. Lee J, et al. Immunohistochemical localization of heat shock protein 27 in the retina of pigs. Neurosci Lett. 2006;406(3):227–31.

    Article  PubMed  CAS  Google Scholar 

  7. Hightower LE. Cultured animal cells exposed to amino acid analogues or puromycin rapidly synthesize several polypeptides. J Cell Physiol. 1980;102(3):407–27.

    Article  PubMed  CAS  Google Scholar 

  8. Gehrmann M, et al. Dual function of membrane-bound heat shock protein 70 (Hsp70), Bag-4, and Hsp40: protection against radiation-induced effects and target structure for natural killer cells. Cell Death Differ. 2005;12(1):38–51.

    Article  PubMed  CAS  Google Scholar 

  9. Gehrmann M, et al. Effects of antineoplastic agents on cytoplasmic and membrane-bound heat shock protein 70 (Hsp70) levels. Biol Chem. 2002;383(11):1715–25.

    Article  PubMed  CAS  Google Scholar 

  10. Ciocca DR, et al. Hsp25 and Hsp70 in rodent tumors treated with doxorubicin and lovastatin. Cell Stress Chaperones. 2003;8(1):26–36.

    Article  PubMed  CAS  Google Scholar 

  11. Gehrmann M, et al. Differential up-regulation of cytosolic and membrane-bound heat shock protein 70 in tumor cells by anti-inflammatory drugs. Clin Cancer Res. 2004;10(10):3354–64.

    Article  PubMed  CAS  Google Scholar 

  12. Fuller KJ, et al. Cancer and the heat shock response. Eur J Cancer. 1994;30A(12):1884–91.

    Article  PubMed  CAS  Google Scholar 

  13. Tezel G, Hernandez R, Wax MB. Immunostaining of heat shock proteins in the retina and optic nerve head of normal and glaucomatous eyes. Arch Ophthalmol. 2000;118(4):511–8.

    PubMed  CAS  Google Scholar 

  14. Sakai M, et al. Immunolocalization of heat shock proteins in the retina of normal monkey eyes and monkey eyes with laser-induced glaucoma. Jpn J Ophthalmol. 2003;47(1):42–52.

    Article  PubMed  CAS  Google Scholar 

  15. Windisch BK, et al. Induction of heat shock proteins 27 and 72 in retinal ganglion cells after acute pressure-induced ischaemia. Clin Experiment Ophthalmol. 2009;37(3):299–307.

    Article  PubMed  Google Scholar 

  16. Kim JY, Sohn HJ, Seo JH. Characterization of the antigenic phenotype of alphaB-crystallin-expressing peripapillary glial cells in the developing chick retina. Anat Cell Biol. 2011;44(1):35–40.

    Article  PubMed  Google Scholar 

  17. Nishikawa S, et al. A transient expression of alpha B-crystallin in the developing rat retinal pigment epithelium. Invest Ophthalmol Vis Sci. 1994;35(12):4159–64.

    PubMed  CAS  Google Scholar 

  18. Xi J, et al. A comprehensive analysis of the expression of crystallins in mouse retina. Mol Vis. 2003;9:410–9.

    PubMed  CAS  Google Scholar 

  19. Xi JH, Bai F, Andley UP. Reduced survival of lens epithelial cells in the alphaA-crystallin-knockout mouse. J Cell Sci. 2003;116(Pt 6):1073–85.

    Article  PubMed  CAS  Google Scholar 

  20. Andley UP. Crystallins in the eye: function and pathology. Prog Retin Eye Res. 2007;26(1):78–98.

    Article  PubMed  CAS  Google Scholar 

  21. Deretic D, et al. Alpha A- and alpha B-crystallin in the retina. Association with the post-Golgi compartment of frog retinal photoreceptors. J Biol Chem. 1994;269(24):16853–61.

    PubMed  CAS  Google Scholar 

  22. Alge CS, et al. Retinal pigment epithelium is protected against apoptosis by alphaB-crystallin. Invest Ophthalmol Vis Sci. 2002;43(11):3575–82.

    PubMed  Google Scholar 

  23. Nagaraj RH, et al. Dicarbonyl stress and apoptosis of vascular cells: prevention by alphaB-crystallin. Ann N Y Acad Sci. 2005;1043:158–65.

    Article  PubMed  CAS  Google Scholar 

  24. Ousman SS, et al. Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature. 2007;448(7152):474–9.

    Article  PubMed  CAS  Google Scholar 

  25. Sreekumar PG, et al. alphaB crystallin is apically secreted within exosomes by polarized human retinal pigment epithelium and provides neuroprotection to adjacent cells. PLoS One. 2010;5(10):e12578.

    Article  PubMed  Google Scholar 

  26. Aoyama A, et al. Alpha B-crystallin expression in mouse NIH 3 T3 fibroblasts: glucocorticoid responsiveness and involvement in thermal protection. Mol Cell Biol. 1993;13(3):1824–35.

    PubMed  CAS  Google Scholar 

  27. Sakaguchi H, et al. Intense light exposure changes the crystallin content in retina. Exp Eye Res. 2003;76(1):131–3.

    Article  PubMed  CAS  Google Scholar 

  28. Vazquez-Chona F, Song BK, Geisert Jr EE. Temporal changes in gene expression after injury in the rat retina. Invest Ophthalmol Vis Sci. 2004;45(8):2737–46.

    Article  PubMed  Google Scholar 

  29. Zabel C, et al. Comparative proteomics in neurodegenerative and non-neurodegenerative diseases suggest nodal point proteins in regulatory networking. J Proteome Res. 2006;5(8):1948–58.

    Article  PubMed  CAS  Google Scholar 

  30. Rao NA, et al. Elevated retina-specific expression of the small heat shock protein, alphaA-crystallin, is associated with photoreceptor protection in experimental uveitis. Invest Ophthalmol Vis Sci. 2008;49(3):1161–71.

    Article  PubMed  Google Scholar 

  31. Kumar PA, et al. Elevated expression of alphaA- and alphaB-crystallins in streptozotocin-induced diabetic rat. Arch Biochem Biophys. 2005;444(2):77–83.

    Article  PubMed  CAS  Google Scholar 

  32. Fujii N, et al. Age-related changes of alpha-crystallin aggregate in human lens. Amino Acids. 2007;32(1):87–94.

    Article  PubMed  CAS  Google Scholar 

  33. Brady JP, et al. Targeted disruption of the mouse alpha A-crystallin gene induces cataract and cytoplasmic inclusion bodies containing the small heat shock protein alpha B-crystallin. Proc Natl Acad Sci USA. 1997;94(3):884–9.

    Article  PubMed  CAS  Google Scholar 

  34. Bagchi M, Katar M, Maisel H. Heat shock proteins of adult and embryonic human ocular lenses. J Cell Biochem. 2002;84(2):278–84.

    Article  PubMed  CAS  Google Scholar 

  35. Bagchi M, et al. Heat shock proteins of chicken lens. J Cell Biochem. 2001;82(3):409–14.

    Article  PubMed  CAS  Google Scholar 

  36. Ren S, et al. Physiological expression of lens alpha-, beta-, and gamma-crystallins in murine and human corneas. Mol Vis. 2010;16:2745–52.

    PubMed  CAS  Google Scholar 

  37. Hansen L, et al. Genetic heterogeneity in microcornea–cataract: five novel mutations in CRYAA, CRYGD, and GJA8. Invest Ophthalmol Vis Sci. 2007;48(9):3937–44.

    Article  PubMed  Google Scholar 

  38. Gain P, et al. In situ immunohistochemical study of Bcl-2 and heat shock proteins in human corneal endothelial cells during corneal storage. Br J Ophthalmol. 2001;85(8):996–1000.

    Article  PubMed  CAS  Google Scholar 

  39. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376(9735):124–36.

    Article  PubMed  Google Scholar 

  40. Kim YH, et al. Protein kinase C delta regulates anti-apoptotic alphaB-crystallin in the retina of type 2 diabetes. Neurobiol Dis. 2007;28(3):293–303.

    Article  PubMed  CAS  Google Scholar 

  41. Wang YD, et al. Comparative proteome analysis of neural retinas from type 2 diabetic rats by two-dimensional electrophoresis. Curr Eye Res. 2007;32(10):891–901.

    Article  PubMed  CAS  Google Scholar 

  42. Fort PE, et al. The retinal proteome in experimental diabetic retinopathy: up-regulation of crystallins and reversal by systemic and periocular insulin. Mol Cell Proteomics. 2009;8(4):767–79.

    Article  PubMed  CAS  Google Scholar 

  43. Quin GG, et al. Proteome map of normal rat retina and comparison with the proteome of diabetic rat retina: new insight in the pathogenesis of diabetic retinopathy. Proteomics. 2007;7(15):2636–50.

    Article  PubMed  CAS  Google Scholar 

  44. Losiewicz MK, Fort PE. Diabetes impairs the neuroprotective properties of retinal alpha-crystallins. Invest Ophthalmol Vis Sci. 2011;52(9):5034–42.

    Article  PubMed  CAS  Google Scholar 

  45. Burt D, et al. Anti-heat shock protein 27 antibody levels and diabetes complications in the EURODIAB study. Diabetes Care. 2009;32(7):1269–71.

    Article  PubMed  CAS  Google Scholar 

  46. Garlick RL, et al. Nonenzymatic glycation of human lens crystallin. Effect of aging and diabetes mellitus. J Clin Invest. 1984;74(5):1742–9.

    Article  PubMed  CAS  Google Scholar 

  47. Nakayama H, et al. Immunochemical detection of advanced glycation end products in lens crystallins from streptozocin-induced diabetic rat. Diabetes. 1993;42(2):345–50.

    Article  PubMed  CAS  Google Scholar 

  48. van Heyningen R, Harding JJ. Do aspirin-like analgesics protect against cataract? A case–control study. Lancet. 1986;1(8490):1111–3.

    Article  PubMed  Google Scholar 

  49. Reid J, Macdougall AI, Andrews MM. Aspirin and diabetes mellitus. Br Med J. 1957;2(5053):1071–4.

    Article  PubMed  CAS  Google Scholar 

  50. Bornstein J, Meade BW, Smith MJ. Salicylates and carbohydrate metabolism. Nature. 1952;169(4290):115–6.

    Article  PubMed  CAS  Google Scholar 

  51. Clark JI, Muchowski PJ. Small heat-shock proteins and their potential role in human disease. Curr Opin Struct Biol. 2000;10(1):52–9.

    Article  PubMed  CAS  Google Scholar 

  52. Dobson CM, Karplus M. The fundamentals of protein folding: bringing together theory and experiment. Curr Opin Struct Biol. 1999;9(1):92–101.

    Article  PubMed  CAS  Google Scholar 

  53. Ko JA, et al. Up-regulation of HSP70 by the fibronectin-derived peptide PHSRN in human corneal epithelial cells. Biochem Biophys Res Commun. 2008;370(3):424–8.

    Article  PubMed  CAS  Google Scholar 

  54. McMurtry AL, et al. Expression of HSP70 in healing wounds of diabetic and nondiabetic mice. J Surg Res. 1999;86(1):36–41.

    Article  PubMed  CAS  Google Scholar 

  55. Xu KP, et al. High glucose suppresses epidermal growth factor receptor/phosphatidylinositol 3-kinase/Akt signaling pathway and attenuates corneal epithelial wound healing. Diabetes. 2009;58(5):1077–85.

    Article  PubMed  CAS  Google Scholar 

  56. Lassen N, et al. The role of corneal crystallins in the cellular defense mechanisms against oxidative stress. Semin Cell Dev Biol. 2008;19(2):100–12.

    Article  PubMed  CAS  Google Scholar 

  57. Hammes HP, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003;9(3):294–9.

    Article  PubMed  CAS  Google Scholar 

  58. Sax CM, Piatigorsky J. Expression of the alpha-crystallin/small heat-shock protein/molecular chaperone genes in the lens and other tissues. Adv Enzymol Relat Areas Mol Biol. 1994;69:155–201.

    PubMed  CAS  Google Scholar 

  59. Ilagan JG, et al. Regulation of alphaA-crystallin gene expression. Lens specificity achieved through the differential placement of similar transcriptional control elements in mouse and chicken. J Biol Chem. 1999;274(28):19973–8.

    Article  PubMed  CAS  Google Scholar 

  60. Morimoto RI. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev. 1998;12(24):3788–96.

    Article  PubMed  CAS  Google Scholar 

  61. Wu C. Heat shock transcription factors: structure and regulation. Annu Rev Cell Dev Biol. 1995;11:441–69.

    Article  PubMed  CAS  Google Scholar 

  62. Kirbach BB, Golenhofen N. Differential expression and induction of small heat shock proteins in rat brain and cultured hippocampal neurons. J Neurosci Res. 2011;89(2):162–75.

    Article  PubMed  CAS  Google Scholar 

  63. Saraswathy S, Rao NA. Posttranslational modification of differentially expressed mitochondrial proteins in the retina during early experimental autoimmune uveitis. Mol Vis. 2011;17:1814–21.

    PubMed  CAS  Google Scholar 

  64. Nagaraj RH, et al. Enhancement of chaperone function of alpha-crystallin by methylglyoxal modification. Biochemistry. 2003;42(36):10746–55.

    Article  PubMed  CAS  Google Scholar 

  65. Hoppe G, et al. Protein s-glutathionylation in retinal pigment epithelium converts heat shock protein 70 to an active chaperone. Exp Eye Res. 2004;78(6):1085–92.

    Article  PubMed  CAS  Google Scholar 

  66. Perry RE, Swamy MS, Abraham EC. Progressive changes in lens crystallin glycation and high-molecular-weight aggregate formation leading to cataract development in streptozotocin-diabetic rats. Exp Eye Res. 1987;44(2):269–82.

    Article  PubMed  CAS  Google Scholar 

  67. Swamy MS, et al. Glycation mediated lens crystallin aggregation and cross-linking by various sugars and sugar phosphates in vitro. Exp Eye Res. 1993;56(2):177–85.

    Article  PubMed  CAS  Google Scholar 

  68. Scroggins BT, et al. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol Cell. 2007;25(1):151–9.

    Article  PubMed  CAS  Google Scholar 

  69. Cherian M, Abraham EC. Diabetes affects alpha-crystallin chaperone function. Biochem Biophys Res Commun. 1995;212(1):184–9.

    Article  PubMed  CAS  Google Scholar 

  70. Shroff NP, et al. Mutation of R116C results in highly oligomerized alpha A-crystallin with modified structure and defective chaperone-like function. Biochemistry. 2000;39(6):1420–6.

    Article  PubMed  CAS  Google Scholar 

  71. Ito H, et al. Phosphorylation of alphaB-crystallin in response to various types of stress. J Biol Chem. 1997;272(47):29934–41.

    Article  PubMed  CAS  Google Scholar 

  72. Barber AJ, et al. Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3. J Biol Chem. 2001;276(35):32814–21.

    Article  PubMed  CAS  Google Scholar 

  73. Li DW, et al. Calcium-activated RAF/MEK/ERK signaling pathway mediates p53-dependent apoptosis and is abrogated by alpha B-crystallin through inhibition of RAS activation. Mol Biol Cell. 2005;16(9):4437–53.

    Article  PubMed  CAS  Google Scholar 

  74. Liu B, Bhat M, Nagaraj RH. AlphaB-crystallin inhibits glucose-induced apoptosis in vascular endothelial cells. Biochem Biophys Res Commun. 2004;321(1):254–8.

    Article  PubMed  CAS  Google Scholar 

  75. Lawler ML, Brun YV. A molecular beacon defines bacterial cell asymmetry. Cell. 2006;124(5):891–3.

    Article  PubMed  CAS  Google Scholar 

  76. Kamradt MC, et al. The small heat shock protein alpha B-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3. J Biol Chem. 2005;280(12):11059–66.

    Article  PubMed  CAS  Google Scholar 

  77. Mao YW, et al. Human alphaA- and alphaB-crystallins bind to Bax and Bcl-X(S) to sequester their translocation during staurosporine-induced apoptosis. Cell Death Differ. 2004;11(5):512–26.

    Article  PubMed  CAS  Google Scholar 

  78. Whiston EA, et al. alphaB-crystallin protects retinal tissue during Staphylococcus aureus-induced endophthalmitis. Infect Immun. 2008;76(4):1781–90.

    Article  PubMed  CAS  Google Scholar 

  79. Chen L, et al. Associations of seroreactivity against crystallin proteins with disease activity and cataract in patients with uveitis. Invest Ophthalmol Vis Sci. 2008;49(10):4476–81.

    Article  PubMed  Google Scholar 

  80. Arac A, et al. Systemic augmentation of {alpha}B-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation. Proc Natl Acad Sci USA. 2011;108(32):13287–92.

    Article  PubMed  CAS  Google Scholar 

  81. Pangratz-Fuehrer S, et al. Functional rescue of experimental ischemic optic neuropathy with alphaB-crystallin. Eye (Lond). 2011;25(6):809–17.

    Article  CAS  Google Scholar 

  82. Santhoshkumar P, Murugesan R, Sharma KK. Deletion of (54)FLRAPSWF(61) residues decreases the oligomeric size and enhances the chaperone function of alphaB-crystallin. Biochemistry. 2009;48(23):5066–73.

    Article  PubMed  CAS  Google Scholar 

  83. Bhattacharyya J, et al. Mini-alphaB-crystallin: a functional element of alphaB-crystallin with chaperone-like activity. Biochemistry. 2006;45(9):3069–76.

    Article  PubMed  CAS  Google Scholar 

  84. Maron R, et al. Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation. 2002;106(13):1708–15.

    Article  PubMed  CAS  Google Scholar 

  85. Ishii Y, Kwong JM, Caprioli J. Retinal ganglion cell protection with geranylgeranylacetone, a heat shock protein inducer, in a rat glaucoma model. Invest Ophthalmol Vis Sci. 2003;44(5):1982–92.

    Article  PubMed  Google Scholar 

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  1. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA

    Erich A. Heise & Patrice E. Fort

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  1. Erich A. Heise
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  2. Patrice E. Fort
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Correspondence to Patrice E. Fort.

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Heise, E.A., Fort, P.E. Impact of diabetes on alpha-crystallins and other heat shock proteins in the eye. j ocul biol dis inform 4, 62–69 (2011). https://doi.org/10.1007/s12177-011-9073-7

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  • DOI: https://doi.org/10.1007/s12177-011-9073-7

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