Retinal inflammation in murine models of type 1 and type 2 diabetes with diabetic retinopathy.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0006777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0428 (Electronic) Linking ISSN: 0012186X NLM ISO Abbreviation: Diabetologia Subsets: MEDLINE

Original Publication: Berlin Springer Verlag

Diabetic Retinopathy*/genetics ; Diabetic Retinopathy*/metabolism ; Diabetes Mellitus, Type 2*/metabolism ; Diabetes Mellitus, Type 1*/metabolism ; Diabetes Mellitus, Experimental*/metabolism; Mice ; Animals ; Disease Models, Animal ; Endothelial Cells/metabolism ; Gliosis/complications ; Gliosis/metabolism ; Retina/metabolism ; Inflammation/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Pericytes/metabolism

Aims/hypothesis: The loss of pericytes surrounding the retinal vasculature in early diabetic retinopathy underlies changes to the neurovascular unit that lead to more destructive forms of the disease. However, it is unclear which changes lead to loss of retinal pericytes. This study investigated the hypothesis that chronic increases in one or more inflammatory factors mitigate the signalling pathways needed for pericyte survival.
Methods: Loss of pericytes and levels of inflammatory markers at the mRNA and protein levels were investigated in two genetic models of diabetes, Ins2 ^Akita/+ (a model of type 1 diabetes) and Lepr ^db/db (a model of type 2 diabetes), at early stages of diabetic retinopathy. In addition, changes that accompany gliosis and the retinal vasculature were determined. Finally, changes in retinal pericytes chronically incubated with vehicle or increasing amounts of IFNγ were investigated to determine the effects on pericyte survival. The numbers of pericytes, microglia, astrocytes and endothelial cells in retinal flatmounts were determined by immunofluorescence. Protein and mRNA levels of inflammatory factors were determined using multiplex ELISAs and quantitative reverse transcription PCR (qRT-PCR). The effects of IFNγ on the murine retinal pericyte survival-related platelet-derived growth factor receptor β (PDGFRβ) signalling pathway were investigated by western blot analysis. Finally, the levels of cell death-associated protein kinase C isoform delta (PKCδ) and cleaved caspase 3 (CC3) in pericytes were determined by western blot analysis and immunocytochemistry.
Results: The essential findings of this study were that both type 1 and 2 diabetes were accompanied by a similar progression of retinal pericyte loss, as well as gliosis. However, inflammatory factor expression was dissimilar in the two models of diabetes, with peak expression occurring at different ages for each model. Retinal vascular changes were more severe in the type 2 diabetes model. Chronic incubation of murine retinal pericytes with IFNγ decreased PDGFRβ signalling and increased the levels of active PKCδ and CC3.
Conclusions/interpretation: We conclude that retinal inflammation is involved in and sustains pericyte loss as diabetic retinopathy progresses. Moreover, IFNγ plays a critical role in reducing pericyte survival in the retina by reducing activation of the PDGFRβ signalling pathway and increasing PKCδ levels and pericyte apoptosis.
(© 2023. The Author(s).)

Diabetes. 2002 Oct;51(10):3107-12. (PMID: 12351455)
Nat Med. 2009 Nov;15(11):1298-306. (PMID: 19881493)
Neural Regen Res. 2023 May;18(5):976-982. (PMID: 36254977)
Front Immunol. 2019 Aug 20;10:1975. (PMID: 31481963)
J Neuroinflammation. 2017 Apr 5;14(1):76. (PMID: 28381236)
Cardiovasc Diabetol. 2019 Jun 4;18(1):72. (PMID: 31164120)
Kidney Int. 2004 Jan;65(1):116-28. (PMID: 14675042)
World J Diabetes. 2021 Jul 15;12(7):939-953. (PMID: 34326947)
Int J Mol Sci. 2018 Mar 22;19(4):. (PMID: 29565290)
Cell Death Dis. 2014 Jan 09;5:e986. (PMID: 24407239)
Mediators Inflamm. 2000;9(5):243-8. (PMID: 11200365)
Invest Ophthalmol Vis Sci. 2011 Mar 10;52(3):1336-44. (PMID: 21212173)
Transl Vis Sci Technol. 2021 Apr 1;10(4):20. (PMID: 34003998)
J Ophthalmic Vis Res. 2014 Jul-Sep;9(3):362-73. (PMID: 25667739)
BMJ Open Ophthalmol. 2021 Jun 30;6(1):e000717. (PMID: 34263060)
Eur Cardiol. 2019 Apr;14(1):50-59. (PMID: 31131037)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
FASEB J. 2020 Dec;34(12):15659-15674. (PMID: 33131091)
Cell Signal. 2011 Feb;23(2):425-35. (PMID: 20955790)
Eur J Immunol. 2012 Aug;42(8):2010-8. (PMID: 22865049)
Eye (Lond). 2019 Apr;33(4):600-609. (PMID: 30401898)
Front Immunol. 2020 Nov 06;11:564077. (PMID: 33240260)
Lancet Diabetes Endocrinol. 2019 Feb;7(2):140-149. (PMID: 30005958)
Invest Ophthalmol Vis Sci. 2020 Sep 1;61(11):2. (PMID: 32870245)
Pharmacol Ther. 2017 Mar;171:30-42. (PMID: 27916653)
Invest Ophthalmol Vis Sci. 2004 Nov;45(11):4161-6. (PMID: 15505070)
J Neurosci. 2014 Jul 23;34(30):10109-21. (PMID: 25057212)
Neuron. 2014 Jan 22;81(2):229-48. (PMID: 24462092)
Vision Res. 2017 Oct;139:7-14. (PMID: 28412095)
Int J Biol Sci. 2013;9(1):94-107. (PMID: 23355795)
Am J Physiol Cell Physiol. 2009 Apr;296(4):C724-34. (PMID: 19193867)
BMJ Open. 2019 Mar 3;9(3):e022188. (PMID: 30833309)
Exp Ther Med. 2018 Oct;16(4):3539-3545. (PMID: 30250524)
Curr Eye Res. 2019 May;44(5):564-574. (PMID: 30644770)
Am J Physiol Renal Physiol. 2006 Jan;290(1):F214-22. (PMID: 16118394)
Diabetes Metab. 2019 Dec;45(6):517-527. (PMID: 31005756)
Am J Pathol. 2004 Apr;164(4):1263-73. (PMID: 15039215)
Acta Ophthalmol. 2013 Aug;91(5):445-52. (PMID: 22520269)
PLoS One. 2011;6(11):e27385. (PMID: 22110636)
Dis Model Mech. 2012 Jul;5(4):444-56. (PMID: 22730475)
Front Mol Neurosci. 2009 Jul 09;2:6. (PMID: 19924257)
Curr Eye Res. 2012 May;37(5):416-20. (PMID: 22409294)
Mol Vis. 2014 Jul 31;20:1085-108. (PMID: 25253985)
Eye Vis (Lond). 2021 May 1;8(1):15. (PMID: 33931128)

P30 EY016665 United States EY NEI NIH HHS; R15 EY033968 United States EY NEI NIH HHS; R01 EY030076 United States EY NEI NIH HHS; R01 EY032543 United States EY NEI NIH HHS

Keywords: Diabetic retinopathy; Gliosis; IFN gamma; IFNγ; Inflammation; PDGFRβ; PKCδ; Pericytes; Platelet-derived growth factor receptor β

0 (RNA, Messenger)

Date Created: 20230905 Date Completed: 20231005 Latest Revision: 20240210

20240210

PMC10541343

10.1007/s00125-023-05995-4

37670018