The roles of uric acid in the pathogenesis of diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

She Xinping , Zhu Dandan ,  Zheng Zhi

Department of Ophthalmology, The First People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China;

Corresponding author：

Zheng Zhi, Email: zzheng88@sjtu.edu.cn

Keywords：

Uric acid; Diabetic retinopathy; Hyperuricimia; Review

DOI：

10.3760/cma.j.issn.1005-1015.2018.04.022

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Uric acid (UA) is the final product of human purine metabolism. As one of the main antioxidants in the body, it can scavenge oxidative radicals. Under the action of oxidative-antioxidant shuttle mechanism, the antioxidant activity of UA can be reversed, causing inflammation and oxidative stress of vascular endothelial cells. Hyperuricemia (HUA) is considered to be one of the major risk factors for diabetes and diabetic nephropathy. The study of HUA in diabetic retinopathy (DR) is also a hot topic. UA can cause retinal vascular sclerosis, and affect the occurrence and development of DR by promoting oxidative stress and inducing neovascularization.

Citation： She Xinping, Zhu Dandan, Zheng Zhi. The roles of uric acid in the pathogenesis of diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2018, 34(4): 401-404. doi: 10.3760/cma.j.issn.1005-1015.2018.04.022 Copy

1.	Silva PS, Cavallerano JD, Sun JK, et al. Effect of systemic medications on onset and progression of diabetic retinopathy[J]. Nat Rev Endocrinol, 2010, 6(9): 494-508. DOI: 10.1038/nrendo.2010.122.
2.	Rajalakshmi R, Prathiba V, Mohan V. Does tight control of systemic factors help in the management of diabetic retinopathy?[J]. Indian J Ophthalmol, 2016, 64(1): 62-68. DOI: 10.4103/0301-4738.178146.
3.	Liang CC, Lin PC, Lee MY, et al. Association of serum uric acid concentration with diabetic retinopathy and albuminuria in Taiwanese patients with type 2 diabetes mellitus[J/OL]. Int J Mol Sci, 2016, 17(8): 1248 [2016-08-02]. https://doi.org/10.3390/ijms17081248. DOI: 10.3390/ijms17081248.
4.	Krizova L, Kalousova M, Kubena A, et al. Increased uric acid and glucose concentrations in vitreous and serum of patients with diabetic macular oedema[J]. Ophthalmic Res, 2011, 46(2): 73-79. DOI: 10.1159/000322994.
5.	Braga TT, Forni MF, Correa-Costa M, et al. Soluble uric acid activates the NLRP3 inflammasome[J/OL]. Sci Rep, 2017, 7: 39884[2017-01-13]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233987/. DOI: 10.1038/srep39884.
6.	Xia J, Wang Z, Zhang F. Association between related purine metabolites and diabetic retinopathy in type 2 diabetic patients[J/OL]. Int J Endocrinol, 2014, 2014: 651050[2014-02-13]. http://dx.doi.org/10.1155/2014/651050.
7.	Zou H, Wang H, Liu T, et al. Protective role of alpha-lipoic acid in hyperuricemia-induced endothelial dysfunction[J]. Exp Ther Med, 2017, 13(6): 3047-3054. DOI: 10.3892/etm.2017.4345.
8.	Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox[J]. Nucleosides Nucleotides Nucleic Acids, 2008, 27(6): 608-619. DOI: 10.1080/15257770802138558.
9.	Ejaz AA, Mu W, Kang DH, et al. Could uric acid have a role in acute renal failure?[J]. Clin J Am Soc Nephrol, 2007, 2(1): 16-21. DOI: 10.2215/CJN.00350106.
10.	Hayden MR, Tyagi SC. Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: the urate redox shuttle[J]. Nutr Metab (Lond), 2004, 1(1): 10. DOI: 10.1186/1743-7075-1-10.
11.	Martinon F, Petrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome[J]. Nature, 2006, 440(7081): 237-241. DOI: 10.1038/nature04516.
12.	Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction[J]. Kidney Int, 2005, 67(5): 1739-1742. DOI: 10.1111/j.1523-1755.2005.00273.x.
13.	Kim TH, Lee SS, Yoo JH, et al. The relationship between the regional abdominal adipose tissue distribution and the serum uric acid levels in people with type 2 diabetes mellitus[J]. Diabetol Metab Syndr, 2012, 4(1): 3. DOI: 10.1186/1758-5996-4-3.
14.	Poudel B, Yadav BK, Kumar A, et al. Serum uric acid level in newly diagnosed essential hypertension in a Nepalese population: a hospital based cross sectional study[J]. Asian Pac J Trop Biomed, 2014, 4(1): 59-64. DOI: 10.1016/S2221-1691(14)60209-4.
15.	Marotta T, Liccardo M, Schettini F, et al. Association of hyperuricemia with conventional cardiovascular risk factors in elderly patients[J]. J Clin Hypertens (Greenwich), 2015, 17(1): 27-32. DOI: 10.1111/jch.12434.
16.	Lee JJ, Yang IH, Kuo HK, et al. Serum uric acid concentration is associated with worsening in severity of diabetic retinopathy among type 2 diabetic patients in Taiwan--a 3-year prospective study[J]. Diabetes Res Clin Pract, 2014, 106(2): 366-372. DOI: 10.1016/j.diabres.2014.07.027.
17.	Zhu Y, Hu Y, Huang T, et al. High uric acid directly inhibits insulin signalling and induces insulin resistance[J]. Biochem Biophys Res Commun, 2014, 447(4): 707-714. DOI: 10.1016/j.bbrc.2014.04.080.
18.	Nejatinamini S, Ataie-Jafari A, Qorbani M, et al. Association between serum uric acid level and metabolic syndrome components[J]. J Diabetes Metab Disord, 2015, 14: 70. DOI: 10.1186/s40200-015-0200-z.
19.	Takir M, Kostek O, Ozkok A, et al. Lowering uric acid with allopurinol improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia[J]. J Investig Med, 2015, 63(8): 924-929. DOI: 10.1097/JIM.0000000000000242.
20.	Kuo CF, Grainge MJ, Mallen C, et al. Comorbidities in patients with gout prior to and following diagnosis: case-control study[J]. Ann Rheum Dis, 2016, 75(1): 210-217. DOI: 10.1136/annrheumdis-2014-206410.
21.	Kohagura K, Kochi M, Miyagi T, et al. An association between uric acid levels and renal arteriolopathy in chronic kidney disease: a biopsy-based study[J]. Hypertens Res, 2013, 36(1): 43-49. DOI: 10.1038/hr.2012.135.
22.	Bartakova V, Kuricova K, Pacal L, et al. Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus[J]. J Diabetes Complications, 2016, 30(7): 1300-1307. DOI: 10.1016/j.jdiacomp.2016.06.002.
23.	Tojo A, Asaba K, Onozato ML. Suppressing renal NADPH oxidase to treat diabetic nephropathy[J]. Expert Opin Ther Targets, 2007, 11(8): 1011-1018. DOI: 10.1517/14728222.11.8.1011.
24.	Griffiths M. The mechanism of the diabetogenic action of uric acid[J]. J Biol Chem, 1950, 184(1): 289-298.
25.	Feldman T, Weitzman S, Biedner B. Retinopathy and serum uric acid in diabetics[J]. Harefuah, 1995, 128(11): 681-683.
26.	Navin S, Krishnamurthy N, Ashakiran S, et al. The association of hypomagnesaemia, high normal uricaemia and dyslipidaemia in the patients with diabetic retinopathy[J]. J Clin Diagn Res, 2013, 7(9): 1852-1854. DOI: 10.7860/JCDR/2013/6106.3332.
27.	Kuwata H, Okamura S, Hayashino Y, et al. Serum uric acid levels are associated with increased risk of newly developed diabetic retinopathy among Japanese male patients with type 2 diabetes: a prospective cohort study (diabetes distress and care registry at Tenri[DDCRT 13])[J/OL]. Diabetes Metab Res Rev, 2017, 2017: E1[2017-04-26]. https://doi.org/10.1002/dmrr.2905. DOI: 10.1002/dmrr.2905. [published online ahead of print].
28.	Vinuthinee-Naidu MN, Zunaina E, Azreen-Redzal A, et al. Correlation of retinal nerve fibre layer and macular thickness with serum uric acid among type 2 diabetes mellitus. BMC Ophthalmol, 2017, 17(1): 91. DOI: 10.1186/s12886-017-0486-3.
29.	Krizova L, Kalousova M, Kubena AA, et al. Correlation of vitreous vascular endothelial growth factor and uric acid concentration using optical coherence tomography in diabetic macular edema[J/OL]. J Ophthalmol, 2015, 2015: 478509 [2015-11-17]. http://dx.doi.org/10.1155/2015/478509. DOI: 10.1155/2015/478509.
30.	Gasse P, Riteau N, Charron S, et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis[J]. Am J Respir Crit Care Med, 2009, 179(10): 903-913. DOI: 10.1164/rccm.200808-1274OC.
31.	Spijkerman AM, Gall MA, Tarnow L, et al. Endothelial dysfunction and low-grade inflammation and the progression of retinopathy in type 2 diabetes[J]. Diabet Med, 2007, 24(9): 969-976. DOI: 10.1111/j.1464-5491.2007.02217.x.
32.	Thomas AA, Feng B, Chakrabarti S. A regulator of VEGF in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(1): 470-480. DOI: 10.1167/iovs.16-20569.
33.	Maiuolo J, Oppedisano F, Gratteri S, et al. Regulation of uric acid metabolism and excretion[J]. Int J Cardiol, 2016, 213: 8-14. DOI: 10.1016/j.ijcard.2015.08.109.
34.	Li LX, Lu JX, Shuai HP, et al. Decreased urine uric acid excretion is associated with diabetic retinopathy but not with lower limb atherosclerosis in hospitalized patients with type 2 diabetes[J]. Atherosclerosis, 2015, 242(1): 13-18. DOI: 10.1016/j.atherosclerosis.2015.06.051.
35.	Forcet C, Stein E, Pays L, et al. Molecular identification of a renal urate-anion exchanger that regulates blood urate levels[J]. Nature, 2002, 417(6887): 443-447. DOI: 10.1038/nature742.
36.	Zharikov S, Krotova K, Hu HB, et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells[J]. Am J Physiol Cell Physiol, 2008, 295(5): 1183-1190. DOI: 10.1152/ajpcell.00075.2008.
37.	Dostert C, Pétrilli V, Van Bruggen R, et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica[J]. Science, 2008, 320(5876): 674-677. DOI: 10.1126/science.1156995.
38.	Raap U, Brzoska T, Sohl S, et al. Alpha-melanocyte-stimulating hormone inhibits allergic airway inflammation[J]. J Immunol, 2003, 171(1): 353-359. DOI: 10.4049/jimmunol.171.1.353.
39.	So A, Thorens B. Uric acid transport and disease[J]. J Clin Invest, 2010, 120(6): 1791-1799. DOI: 10.1172/JCI42344.

1. Silva PS, Cavallerano JD, Sun JK, et al. Effect of systemic medications on onset and progression of diabetic retinopathy[J]. Nat Rev Endocrinol, 2010, 6(9): 494-508. DOI: 10.1038/nrendo.2010.122.
2. Rajalakshmi R, Prathiba V, Mohan V. Does tight control of systemic factors help in the management of diabetic retinopathy?[J]. Indian J Ophthalmol, 2016, 64(1): 62-68. DOI: 10.4103/0301-4738.178146.
3. Liang CC, Lin PC, Lee MY, et al. Association of serum uric acid concentration with diabetic retinopathy and albuminuria in Taiwanese patients with type 2 diabetes mellitus[J/OL]. Int J Mol Sci, 2016, 17(8): 1248 [2016-08-02]. https://doi.org/10.3390/ijms17081248. DOI: 10.3390/ijms17081248.
4. Krizova L, Kalousova M, Kubena A, et al. Increased uric acid and glucose concentrations in vitreous and serum of patients with diabetic macular oedema[J]. Ophthalmic Res, 2011, 46(2): 73-79. DOI: 10.1159/000322994.
5. Braga TT, Forni MF, Correa-Costa M, et al. Soluble uric acid activates the NLRP3 inflammasome[J/OL]. Sci Rep, 2017, 7: 39884[2017-01-13]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233987/. DOI: 10.1038/srep39884.
6. Xia J, Wang Z, Zhang F. Association between related purine metabolites and diabetic retinopathy in type 2 diabetic patients[J/OL]. Int J Endocrinol, 2014, 2014: 651050[2014-02-13]. http://dx.doi.org/10.1155/2014/651050.
7. Zou H, Wang H, Liu T, et al. Protective role of alpha-lipoic acid in hyperuricemia-induced endothelial dysfunction[J]. Exp Ther Med, 2017, 13(6): 3047-3054. DOI: 10.3892/etm.2017.4345.
8. Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox[J]. Nucleosides Nucleotides Nucleic Acids, 2008, 27(6): 608-619. DOI: 10.1080/15257770802138558.
9. Ejaz AA, Mu W, Kang DH, et al. Could uric acid have a role in acute renal failure?[J]. Clin J Am Soc Nephrol, 2007, 2(1): 16-21. DOI: 10.2215/CJN.00350106.
10. Hayden MR, Tyagi SC. Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: the urate redox shuttle[J]. Nutr Metab (Lond), 2004, 1(1): 10. DOI: 10.1186/1743-7075-1-10.
11. Martinon F, Petrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome[J]. Nature, 2006, 440(7081): 237-241. DOI: 10.1038/nature04516.
12. Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction[J]. Kidney Int, 2005, 67(5): 1739-1742. DOI: 10.1111/j.1523-1755.2005.00273.x.
13. Kim TH, Lee SS, Yoo JH, et al. The relationship between the regional abdominal adipose tissue distribution and the serum uric acid levels in people with type 2 diabetes mellitus[J]. Diabetol Metab Syndr, 2012, 4(1): 3. DOI: 10.1186/1758-5996-4-3.
14. Poudel B, Yadav BK, Kumar A, et al. Serum uric acid level in newly diagnosed essential hypertension in a Nepalese population: a hospital based cross sectional study[J]. Asian Pac J Trop Biomed, 2014, 4(1): 59-64. DOI: 10.1016/S2221-1691(14)60209-4.
15. Marotta T, Liccardo M, Schettini F, et al. Association of hyperuricemia with conventional cardiovascular risk factors in elderly patients[J]. J Clin Hypertens (Greenwich), 2015, 17(1): 27-32. DOI: 10.1111/jch.12434.
16. Lee JJ, Yang IH, Kuo HK, et al. Serum uric acid concentration is associated with worsening in severity of diabetic retinopathy among type 2 diabetic patients in Taiwan--a 3-year prospective study[J]. Diabetes Res Clin Pract, 2014, 106(2): 366-372. DOI: 10.1016/j.diabres.2014.07.027.
17. Zhu Y, Hu Y, Huang T, et al. High uric acid directly inhibits insulin signalling and induces insulin resistance[J]. Biochem Biophys Res Commun, 2014, 447(4): 707-714. DOI: 10.1016/j.bbrc.2014.04.080.
18. Nejatinamini S, Ataie-Jafari A, Qorbani M, et al. Association between serum uric acid level and metabolic syndrome components[J]. J Diabetes Metab Disord, 2015, 14: 70. DOI: 10.1186/s40200-015-0200-z.
19. Takir M, Kostek O, Ozkok A, et al. Lowering uric acid with allopurinol improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia[J]. J Investig Med, 2015, 63(8): 924-929. DOI: 10.1097/JIM.0000000000000242.
20. Kuo CF, Grainge MJ, Mallen C, et al. Comorbidities in patients with gout prior to and following diagnosis: case-control study[J]. Ann Rheum Dis, 2016, 75(1): 210-217. DOI: 10.1136/annrheumdis-2014-206410.
21. Kohagura K, Kochi M, Miyagi T, et al. An association between uric acid levels and renal arteriolopathy in chronic kidney disease: a biopsy-based study[J]. Hypertens Res, 2013, 36(1): 43-49. DOI: 10.1038/hr.2012.135.
22. Bartakova V, Kuricova K, Pacal L, et al. Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus[J]. J Diabetes Complications, 2016, 30(7): 1300-1307. DOI: 10.1016/j.jdiacomp.2016.06.002.
23. Tojo A, Asaba K, Onozato ML. Suppressing renal NADPH oxidase to treat diabetic nephropathy[J]. Expert Opin Ther Targets, 2007, 11(8): 1011-1018. DOI: 10.1517/14728222.11.8.1011.
24. Griffiths M. The mechanism of the diabetogenic action of uric acid[J]. J Biol Chem, 1950, 184(1): 289-298.
25. Feldman T, Weitzman S, Biedner B. Retinopathy and serum uric acid in diabetics[J]. Harefuah, 1995, 128(11): 681-683.
26. Navin S, Krishnamurthy N, Ashakiran S, et al. The association of hypomagnesaemia, high normal uricaemia and dyslipidaemia in the patients with diabetic retinopathy[J]. J Clin Diagn Res, 2013, 7(9): 1852-1854. DOI: 10.7860/JCDR/2013/6106.3332.
27. Kuwata H, Okamura S, Hayashino Y, et al. Serum uric acid levels are associated with increased risk of newly developed diabetic retinopathy among Japanese male patients with type 2 diabetes: a prospective cohort study (diabetes distress and care registry at Tenri[DDCRT 13])[J/OL]. Diabetes Metab Res Rev, 2017, 2017: E1[2017-04-26]. https://doi.org/10.1002/dmrr.2905. DOI: 10.1002/dmrr.2905. [published online ahead of print].
28. Vinuthinee-Naidu MN, Zunaina E, Azreen-Redzal A, et al. Correlation of retinal nerve fibre layer and macular thickness with serum uric acid among type 2 diabetes mellitus. BMC Ophthalmol, 2017, 17(1): 91. DOI: 10.1186/s12886-017-0486-3.
29. Krizova L, Kalousova M, Kubena AA, et al. Correlation of vitreous vascular endothelial growth factor and uric acid concentration using optical coherence tomography in diabetic macular edema[J/OL]. J Ophthalmol, 2015, 2015: 478509 [2015-11-17]. http://dx.doi.org/10.1155/2015/478509. DOI: 10.1155/2015/478509.
30. Gasse P, Riteau N, Charron S, et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis[J]. Am J Respir Crit Care Med, 2009, 179(10): 903-913. DOI: 10.1164/rccm.200808-1274OC.
31. Spijkerman AM, Gall MA, Tarnow L, et al. Endothelial dysfunction and low-grade inflammation and the progression of retinopathy in type 2 diabetes[J]. Diabet Med, 2007, 24(9): 969-976. DOI: 10.1111/j.1464-5491.2007.02217.x.
32. Thomas AA, Feng B, Chakrabarti S. A regulator of VEGF in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(1): 470-480. DOI: 10.1167/iovs.16-20569.
33. Maiuolo J, Oppedisano F, Gratteri S, et al. Regulation of uric acid metabolism and excretion[J]. Int J Cardiol, 2016, 213: 8-14. DOI: 10.1016/j.ijcard.2015.08.109.
34. Li LX, Lu JX, Shuai HP, et al. Decreased urine uric acid excretion is associated with diabetic retinopathy but not with lower limb atherosclerosis in hospitalized patients with type 2 diabetes[J]. Atherosclerosis, 2015, 242(1): 13-18. DOI: 10.1016/j.atherosclerosis.2015.06.051.
35. Forcet C, Stein E, Pays L, et al. Molecular identification of a renal urate-anion exchanger that regulates blood urate levels[J]. Nature, 2002, 417(6887): 443-447. DOI: 10.1038/nature742.
36. Zharikov S, Krotova K, Hu HB, et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells[J]. Am J Physiol Cell Physiol, 2008, 295(5): 1183-1190. DOI: 10.1152/ajpcell.00075.2008.
37. Dostert C, Pétrilli V, Van Bruggen R, et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica[J]. Science, 2008, 320(5876): 674-677. DOI: 10.1126/science.1156995.
38. Raap U, Brzoska T, Sohl S, et al. Alpha-melanocyte-stimulating hormone inhibits allergic airway inflammation[J]. J Immunol, 2003, 171(1): 353-359. DOI: 10.4049/jimmunol.171.1.353.
39. So A, Thorens B. Uric acid transport and disease[J]. J Clin Invest, 2010, 120(6): 1791-1799. DOI: 10.1172/JCI42344.

Previous Article
大动脉炎合并眼部病变一例
Next Article
Research progress of optical coherence tomography combined with microperimetry in diabetic macular edema

Chinese Journal of Ocular Fundus Diseases

The roles of uric acid in the pathogenesis of diabetic retinopathy

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content