Vitamin D Protects Against Diabetic Retinopathy by Inhibiting High-Glucose-Induced Activation of the ROS/TXNIP/NLRP3 Inflammasome Pathway

Overview

Journal J Diabetes Res

Publisher Wiley

Specialty Endocrinology

Date 2018 Apr 24

PMID 29682582

Citations 77

Authors

Li Lu

Qianyi Lu

Wei Chen

Jingwen Li

Chunxia Li

Zhi Zheng

Affiliations

Soon will be listed here.

Abstract

Purpose: This study aimed to evaluate the mechanisms underlying the effects of 1,25-dihydroxyvitamin D (vitamin D) on diabetes-induced retinal vascular damage and retinal vascular endothelial cell apoptosis.

Methods: Diabetic and control rats were randomly assigned to receive vitamin D or vehicle for 6 months. Additionally, human retinal microvascular endothelial cells (HRMECs) were incubated in normal or high-glucose medium with or without vitamin D. Morphological changes in retinal tissues and retinal vascular permeability were examined, and cellular apoptosis was detected by fluorescence staining. Intracellular reactive oxygen species (ROS) levels were determined using fluorescent probes. Proteins were examined by Western blotting.

Results: Vitamin D significantly downregulated intracellular ROS and inhibited TRX-interacting protein (TXNIP)/NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway activation. Additionally, vitamin D reduced vascular endothelial growth factor (VEGF) expression and the Bax/Bcl-2 ratio. These changes were associated with retinal recovery and with decreases in retinal vascular permeability and retinal capillary cell apoptosis.

Conclusions: Vitamin D decreases diabetes-induced ROS and exerts protective effects against retinal vascular damage and cell apoptosis in association with inhibition of the ROS/TXNIP/NLRP3 inflammasome pathway. Understanding the mechanisms of action of vitamin D has important implications for preventing and treating inflammatory-related illnesses such as diabetic retinopathy.

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References

Kaur H, Donaghue K, Chan A, Benitez-Aguirre P, Hing S, Lloyd M . Vitamin D deficiency is associated with retinopathy in children and adolescents with type 1 diabetes. Diabetes Care. 2011; 34(6):1400-2. PMC: 3114351. DOI: 10.2337/dc11-0103. View

Devi T, Lee I, Huttemann M, Kumar A, Nantwi K, Singh L . TXNIP links innate host defense mechanisms to oxidative stress and inflammation in retinal Muller glia under chronic hyperglycemia: implications for diabetic retinopathy. Exp Diabetes Res. 2012; 2012:438238. PMC: 3313582. DOI: 10.1155/2012/438238. View

Ting J, Willingham S, Bergstralh D . NLRs at the intersection of cell death and immunity. Nat Rev Immunol. 2008; 8(5):372-9. DOI: 10.1038/nri2296. View

Adamis A . Is diabetic retinopathy an inflammatory disease?. Br J Ophthalmol. 2002; 86(4):363-5. PMC: 1771111. DOI: 10.1136/bjo.86.4.363. View

Longo-Mbenza B, Muaka M, Masamba W, Muizila Kini L, Longo Phemba I, Kibokela Ndembe D . Retinopathy in non diabetics, diabetic retinopathy and oxidative stress: a new phenotype in Central Africa?. Int J Ophthalmol. 2014; 7(2):293-301. PMC: 4003085. DOI: 10.3980/j.issn.2222-3959.2014.02.18. View

Lawlor K, Vince J . Ambiguities in NLRP3 inflammasome regulation: is there a role for mitochondria?. Biochim Biophys Acta. 2013; 1840(4):1433-40. DOI: 10.1016/j.bbagen.2013.08.014. View

Aksoy H, Akcay F, Kurtul N, Baykal O, Avci B . Serum 1,25 dihydroxy vitamin D (1,25(OH)2D3), 25 hydroxy vitamin D (25(OH)D) and parathormone levels in diabetic retinopathy. Clin Biochem. 2000; 33(1):47-51. DOI: 10.1016/s0009-9120(99)00085-5. View

Taverna M, Selam J, Slama G . Association between a protein polymorphism in the start codon of the vitamin D receptor gene and severe diabetic retinopathy in C-peptide-negative type 1 diabetes. J Clin Endocrinol Metab. 2005; 90(8):4803-8. DOI: 10.1210/jc.2004-2407. View

Kowluru R, Mohammad G, Santos J, Tewari S, Zhong Q . Interleukin-1β and mitochondria damage, and the development of diabetic retinopathy. J Ocul Biol Dis Infor. 2012; 4(1-2):3-9. PMC: 3342404. DOI: 10.1007/s12177-011-9074-6. View

10.

Kern T . Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res. 2008; 2007:95103. PMC: 2216058. DOI: 10.1155/2007/95103. View

11.

Plum L, Deluca H . Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010; 9(12):941-55. DOI: 10.1038/nrd3318. View

12.

Zhong X, Du Y, Lei Y, Liu N, Guo Y, Pan T . Effects of vitamin D receptor gene polymorphism and clinical characteristics on risk of diabetic retinopathy in Han Chinese type 2 diabetes patients. Gene. 2015; 566(2):212-6. DOI: 10.1016/j.gene.2015.04.045. View

13.

Guillot X, Semerano L, Saidenberg-Kermanach N, Falgarone G, Boissier M . Vitamin D and inflammation. Joint Bone Spine. 2010; 77(6):552-7. DOI: 10.1016/j.jbspin.2010.09.018. View

14.

Vincent J, Mohr S . Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes. 2006; 56(1):224-30. DOI: 10.2337/db06-0427. View

15.

Zheng Z, Chen H, Wang H, Ke B, Zheng B, Li Q . Improvement of retinal vascular injury in diabetic rats by statins is associated with the inhibition of mitochondrial reactive oxygen species pathway mediated by peroxisome proliferator-activated receptor gamma coactivator 1alpha. Diabetes. 2010; 59(9):2315-25. PMC: 2927955. DOI: 10.2337/db10-0638. View

16.

Brownlee M . The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005; 54(6):1615-25. DOI: 10.2337/diabetes.54.6.1615. View

17.

Leal E, Martins J, Voabil P, Liberal J, Chiavaroli C, Bauer J . Calcium dobesilate inhibits the alterations in tight junction proteins and leukocyte adhesion to retinal endothelial cells induced by diabetes. Diabetes. 2010; 59(10):2637-45. PMC: 3279541. DOI: 10.2337/db09-1421. View

18.

Brownlee M . Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414(6865):813-20. DOI: 10.1038/414813a. View

19.

Patrick P, Visintainer P, Shi Q, Weiss I, Brand D . Vitamin D and retinopathy in adults with diabetes mellitus. Arch Ophthalmol. 2012; 130(6):756-60. DOI: 10.1001/archophthalmol.2011.2749. View

20.

Shimo N, Yasuda T, Kaneto H, Katakami N, Kuroda A, Sakamoto F . Vitamin D deficiency is significantly associated with retinopathy in young Japanese type 1 diabetic patients. Diabetes Res Clin Pract. 2014; 106(2):e41-3. DOI: 10.1016/j.diabres.2014.08.005. View