Skip to main content
Top
Published in: International Ophthalmology 4/2020

01-04-2020 | Diabetic Retinopathy | Original Paper

Hydrogen sulfide serves as a biomarker in the anterior segment of patients with diabetic retinopathy

Authors: Yuyi Han, Xiaoqian Zhang, Zhiyin Zhou, Mengxi Yu, Qiuhong Wang, Jin Yao, Yi Han

Published in: International Ophthalmology | Issue 4/2020

Login to get access

Abstract

Objective

The present study aims to determine hydrogen sulfide (H2S) concentrations of the aqueous humor from patients with diabetic retinopathy (DR) to compare its levels in the anterior segments, also to investigate its effect on the retinal microvascular endothelial cells under high glucose condition.

Methods

AH samples were collected from patients with proliferative diabetic retinopathy (n = 11), non-proliferative diabetic retinopathy (n = 12) and diabetic patients without DR as controls (n = 12). There were 5 patients with PDR received intraocular anti-VEGF injection (Lucentis). Cultured RF/6A cells were grouped into control group, mannitol group, high glucose group and NaHS co-administrated high glucose group. Concentrations of H2S were detected by chemical assay. Cell apoptosis was evaluated by flow cytometry.

Results

A significantly higher H2S level was observed in AH samples of PDR patients among other groups. The H2S level of DR group was higher than that of control group. Decreased H2S levels in the AH of post-injected PDR patients were observed compared with their AH samples before the anti-VEGF injection. In cell culture, low concentration of NaHS can reverse high-glucose-induced apoptosis of RF/6A cells.

Conclusion

Our study revealed increased H2S levels in the anterior segments of different DR patients. The anti-VEGF injection reduced the H2S level in AH from PDR patients. The study suggested that H2S may serve as a biomarker in the progression of PDR. On the other hand, the H2S donor exerted a protective effect on retinal vascular endothelial cells against high-glucose-induced apoptosis.
Literature
1.
go back to reference Simó R, Hernández C (2015) Novel approaches for treating diabetic retinopathy based on recent pathogenic evidence. Prog Retinal Eye Res 48:160–180 Simó R, Hernández C (2015) Novel approaches for treating diabetic retinopathy based on recent pathogenic evidence. Prog Retinal Eye Res 48:160–180
2.
go back to reference Nolan CJ, Damm P, Prentki M (2011) Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 378(9786):169–181PubMed Nolan CJ, Damm P, Prentki M (2011) Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 378(9786):169–181PubMed
3.
go back to reference Congdon NG, Friedman DS, Thomas L (2003) Important causes of visual impairment in the world today. JAMA 290(15):2057PubMed Congdon NG, Friedman DS, Thomas L (2003) Important causes of visual impairment in the world today. JAMA 290(15):2057PubMed
4.
go back to reference Whiting DR, Leonor G, Clara W, Jonathan S (2011) IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94(3):311–321PubMed Whiting DR, Leonor G, Clara W, Jonathan S (2011) IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94(3):311–321PubMed
5.
go back to reference Yau JWY, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW (2012) Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35(3):556–564PubMedPubMedCentral Yau JWY, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW (2012) Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35(3):556–564PubMedPubMedCentral
6.
go back to reference Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL, Klein R (2004) Retinopathy in diabetes. Diabetes Care 27(1):S84PubMed Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL, Klein R (2004) Retinopathy in diabetes. Diabetes Care 27(1):S84PubMed
7.
go back to reference Akiko G, Masaru I, Toshihiro I, Nanako AK, Yuji T, Yasuhiro I, Mikiko F, Hidenobu T (2013) Frequency and risk factors for neovascular glaucoma after vitrectomy in eyes with proliferative diabetic retinopathy. J Glaucoma 22(7):572–576 Akiko G, Masaru I, Toshihiro I, Nanako AK, Yuji T, Yasuhiro I, Mikiko F, Hidenobu T (2013) Frequency and risk factors for neovascular glaucoma after vitrectomy in eyes with proliferative diabetic retinopathy. J Glaucoma 22(7):572–576
8.
go back to reference Hasnan J, Yusof MI, Damitri TD, Faridah AR, Adenan AS, Norbaini TH (2010) Relationship between apoptotic markers (Bax and Bcl-2) and biochemical markers in type 2 diabetes mellitus. Singap Med J 51(1):50–55 Hasnan J, Yusof MI, Damitri TD, Faridah AR, Adenan AS, Norbaini TH (2010) Relationship between apoptotic markers (Bax and Bcl-2) and biochemical markers in type 2 diabetes mellitus. Singap Med J 51(1):50–55
9.
go back to reference Lu M, Adamis AP (2002) Vascular endothelial growth factor gene regulation and action in diabetic retinopathy. Ophthalmol Clin N Am 15(1):69–79 Lu M, Adamis AP (2002) Vascular endothelial growth factor gene regulation and action in diabetic retinopathy. Ophthalmol Clin N Am 15(1):69–79
10.
go back to reference Liu L, Xu Y, Huang Z, Wang X (2016) Intravitreal ranibizumab injection combined trabeculectomy versus Ahmed valve surgery in the treatment of neovascular glaucoma: assessment of efficacy and complications. BMC Ophthalmol 16(1):65PubMedPubMedCentral Liu L, Xu Y, Huang Z, Wang X (2016) Intravitreal ranibizumab injection combined trabeculectomy versus Ahmed valve surgery in the treatment of neovascular glaucoma: assessment of efficacy and complications. BMC Ophthalmol 16(1):65PubMedPubMedCentral
11.
go back to reference Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J, D'Amore PA, Miller JW (1996) Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol 114(1):66–71PubMed Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J, D'Amore PA, Miller JW (1996) Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol 114(1):66–71PubMed
12.
go back to reference Gologorsky D, Thanos A, Vavvas D (2012) Therapeutic interventions against inflammatory and angiogenic mediators in proliferative diabetic retinopathy. Med Inflam 10:629452 Gologorsky D, Thanos A, Vavvas D (2012) Therapeutic interventions against inflammatory and angiogenic mediators in proliferative diabetic retinopathy. Med Inflam 10:629452
13.
go back to reference Kulkarni M, Njie-Mbye YF, Okpobiri I, Zhao M, Opere CA, Ohia SE (2011) Endogenous production of hydrogen sulfide in isolated bovine eye. Neurochem Res 36(8):1540–1545PubMed Kulkarni M, Njie-Mbye YF, Okpobiri I, Zhao M, Opere CA, Ohia SE (2011) Endogenous production of hydrogen sulfide in isolated bovine eye. Neurochem Res 36(8):1540–1545PubMed
14.
go back to reference Szabo C (2018) A timeline of hydrogen sulfide (H2S) research: from environmental toxin to biological mediator. Biochem Pharmacol 149:5–19PubMed Szabo C (2018) A timeline of hydrogen sulfide (H2S) research: from environmental toxin to biological mediator. Biochem Pharmacol 149:5–19PubMed
15.
go back to reference Zanardo RCO, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, Wallace JL (2006) Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J 20(12):2118–2120PubMed Zanardo RCO, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, Wallace JL (2006) Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J 20(12):2118–2120PubMed
16.
go back to reference Kimura Y, Goto Y, Kimura H (2010) Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antiox Redox Signal 12(1):1 Kimura Y, Goto Y, Kimura H (2010) Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antiox Redox Signal 12(1):1
17.
go back to reference Yan SK, Chang T, Hui W, Wu L, Rui W, Meng QH (2006) Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells. Biochem Biophys Res Commun 351(2):485–491PubMed Yan SK, Chang T, Hui W, Wu L, Rui W, Meng QH (2006) Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells. Biochem Biophys Res Commun 351(2):485–491PubMed
18.
go back to reference Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, Gazi SK, Barrow RK, Yang G, Wang R, Snyder SH (2009) H2S signals through protein S-sulfhydration. Sci Signal 2(96):ra72PubMedPubMedCentral Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, Gazi SK, Barrow RK, Yang G, Wang R, Snyder SH (2009) H2S signals through protein S-sulfhydration. Sci Signal 2(96):ra72PubMedPubMedCentral
19.
go back to reference Ran R, Du L, Zhang X, Chen X, Fang Y, Li Y, Tian H (2014) Elevated hydrogen sulfide levels in vitreous body and plasma in patients with proliferative diabetic retinopathy. Retina 34(10):2003–2009PubMed Ran R, Du L, Zhang X, Chen X, Fang Y, Li Y, Tian H (2014) Elevated hydrogen sulfide levels in vitreous body and plasma in patients with proliferative diabetic retinopathy. Retina 34(10):2003–2009PubMed
20.
go back to reference Papapetropoulos A, Pyriochou A, Altaany Z, Yang G, Marazioti A, Zhou Z, Jeschke MG, Branski LK, Herndon DN, Wang R (2009) Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc Natl Acad Sci USA 106(51):21972PubMed Papapetropoulos A, Pyriochou A, Altaany Z, Yang G, Marazioti A, Zhou Z, Jeschke MG, Branski LK, Herndon DN, Wang R (2009) Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc Natl Acad Sci USA 106(51):21972PubMed
21.
go back to reference Liu Z, Han Y, Li L, Lu H, Meng G, Li X, Shirhan M, Peh MT, Xie L, Zhou S (2013) The hydrogen sulfide donor, GYY4137, exhibits anti-atherosclerotic activity in high fat fed apolipoprotein E−/− mice. Br J Pharmacol 169(8):1795–1809PubMedPubMedCentral Liu Z, Han Y, Li L, Lu H, Meng G, Li X, Shirhan M, Peh MT, Xie L, Zhou S (2013) The hydrogen sulfide donor, GYY4137, exhibits anti-atherosclerotic activity in high fat fed apolipoprotein E−/− mice. Br J Pharmacol 169(8):1795–1809PubMedPubMedCentral
22.
go back to reference Li J, Wang P, Yu S, Zheng Z, Xu X (2012) Calcium entry mediates hyperglycemia-induced apoptosis through Ca(2+)/calmodulin-dependent kinase II in retinal capillary endothelial cells. Mol Vis 18(250):2371PubMedPubMedCentral Li J, Wang P, Yu S, Zheng Z, Xu X (2012) Calcium entry mediates hyperglycemia-induced apoptosis through Ca(2+)/calmodulin-dependent kinase II in retinal capillary endothelial cells. Mol Vis 18(250):2371PubMedPubMedCentral
23.
go back to reference Persa C, Osmotherly K, Chen CW, Moon S, Louabcd MF (2006) The distribution of cystathionine β-synthase (CBS) in the eye: Implication of the presence of a trans-sulfuration pathway for oxidative stress defense. Exp Eye Res 83(4):817–823PubMed Persa C, Osmotherly K, Chen CW, Moon S, Louabcd MF (2006) The distribution of cystathionine β-synthase (CBS) in the eye: Implication of the presence of a trans-sulfuration pathway for oxidative stress defense. Exp Eye Res 83(4):817–823PubMed
24.
go back to reference Winnie WP, Renata S, Nina F, Jan PK, William DE (2010) Comparative localization of cystathionine beta-synthase and cystathionine gamma-lyase in retina: differences between amphibians and mammals. J Comp Neurol 505(2):158–165 Winnie WP, Renata S, Nina F, Jan PK, William DE (2010) Comparative localization of cystathionine beta-synthase and cystathionine gamma-lyase in retina: differences between amphibians and mammals. J Comp Neurol 505(2):158–165
25.
go back to reference Lo Faro ML, Fox B, Whatmore JL, Winyard PG, Whiteman M (2014) Hydrogen sulfide and nitric oxide interactions in inflammation. Nitric Oxide Biol Chem 41(11):38 Lo Faro ML, Fox B, Whatmore JL, Winyard PG, Whiteman M (2014) Hydrogen sulfide and nitric oxide interactions in inflammation. Nitric Oxide Biol Chem 41(11):38
26.
go back to reference Kimura H (2014) The physiological role of hydrogen sulfide and beyond. Nitric Oxide 41:4–10PubMed Kimura H (2014) The physiological role of hydrogen sulfide and beyond. Nitric Oxide 41:4–10PubMed
27.
go back to reference Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, Hassessian H, Wiegand SJ, Rudge J, Yancopoulos GD (2001) VEGF-initiated blood-retinal barrier breakdown in early diabetes. Investig Ophthalmol Visual Sci 42(10):2408 Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, Hassessian H, Wiegand SJ, Rudge J, Yancopoulos GD (2001) VEGF-initiated blood-retinal barrier breakdown in early diabetes. Investig Ophthalmol Visual Sci 42(10):2408
28.
go back to reference Gersztenkorn D, Coletta C, Zhu S, Ha Y, Liu H, Tie H, Zhou J, Szabo C, Zhang W, Motamedi M (2016) Hydrogen sulfide contributes to retinal neovascularization in ischemia-induced retinopathy. Invest Ophthalmol Vis Sci 57(7):3002–3009PubMedPubMedCentral Gersztenkorn D, Coletta C, Zhu S, Ha Y, Liu H, Tie H, Zhou J, Szabo C, Zhang W, Motamedi M (2016) Hydrogen sulfide contributes to retinal neovascularization in ischemia-induced retinopathy. Invest Ophthalmol Vis Sci 57(7):3002–3009PubMedPubMedCentral
29.
go back to reference Liu Y, Zou LP, Du JB, Wong V (2010) Electro-acupuncture protects against hypoxic-ischemic brain-damaged immature rat via hydrogen sulfide as a possible mediator. Neurosci Lett 485(1):74–78PubMed Liu Y, Zou LP, Du JB, Wong V (2010) Electro-acupuncture protects against hypoxic-ischemic brain-damaged immature rat via hydrogen sulfide as a possible mediator. Neurosci Lett 485(1):74–78PubMed
30.
go back to reference Qingbo G, Wen L, Yuantao L, Youfei F, Xiaolei W, Chunxiao Y, Yuan Z, Shunke W, Jia L, Jiajun Z (2015) High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs. Int J Mol Med 35(3):810 Qingbo G, Wen L, Yuantao L, Youfei F, Xiaolei W, Chunxiao Y, Yuan Z, Shunke W, Jia L, Jiajun Z (2015) High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs. Int J Mol Med 35(3):810
31.
go back to reference Monica RF, Virgil A, Kerrison JB, Jablon EP (2009) Ranibizumab for diabetic retinopathy. Curr Diabetes Rev 5(1):47–51 Monica RF, Virgil A, Kerrison JB, Jablon EP (2009) Ranibizumab for diabetic retinopathy. Curr Diabetes Rev 5(1):47–51
32.
go back to reference Ning D, Bing X, Bingsong W, Liqun C (2013) Study of 27 aqueous humor cytokines in patients with type 2 diabetes with or without retinopathy. Mol Vis 19(1623):1734–1746 Ning D, Bing X, Bingsong W, Liqun C (2013) Study of 27 aqueous humor cytokines in patients with type 2 diabetes with or without retinopathy. Mol Vis 19(1623):1734–1746
33.
go back to reference Miller JW, Couter JL, Strauss EC, Ferrara N (2013) Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 120(1):106–114PubMed Miller JW, Couter JL, Strauss EC, Ferrara N (2013) Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 120(1):106–114PubMed
34.
go back to reference Yanrong J, Xiaoying L, Xiaoxin L, Yong T, Kai W (2010) Analysis of the clinical efficacy of intravitreal bevacizumab in the treatment of iris neovascularization caused by proliferative diabetic retinopathy. Acta Ophthalmol 87(7):736–740 Yanrong J, Xiaoying L, Xiaoxin L, Yong T, Kai W (2010) Analysis of the clinical efficacy of intravitreal bevacizumab in the treatment of iris neovascularization caused by proliferative diabetic retinopathy. Acta Ophthalmol 87(7):736–740
35.
go back to reference Ababneh OH, Yousef YA, Gharaibeh AM, Ameerh MA, Abu A-Y, Bdour MD (2013) Intravitreal bevacizumab in the treatment of diabetic ocular neovascularization. Retina 33(4):748–755PubMed Ababneh OH, Yousef YA, Gharaibeh AM, Ameerh MA, Abu A-Y, Bdour MD (2013) Intravitreal bevacizumab in the treatment of diabetic ocular neovascularization. Retina 33(4):748–755PubMed
36.
go back to reference Ip MS, Amitha D, Jill JH, Pamela W, Ehrlich JS (2012) Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol 130(9):1145PubMed Ip MS, Amitha D, Jill JH, Pamela W, Ehrlich JS (2012) Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol 130(9):1145PubMed
37.
go back to reference Gemici B, Elsheikh W, Feitosa KB, Costa SKP, Muscara MN, Wallace JL (2015) H2S-releasing drugs: anti-inflammatory, cytoprotective and chemopreventative potential. Nitric Oxide 46:25–31PubMed Gemici B, Elsheikh W, Feitosa KB, Costa SKP, Muscara MN, Wallace JL (2015) H2S-releasing drugs: anti-inflammatory, cytoprotective and chemopreventative potential. Nitric Oxide 46:25–31PubMed
38.
go back to reference Wang MJ, Cai WJ, Li N, Ding YJ, Chen Y, Zhu YC (2010) The hydrogen sulfide donor NaHS promotes angiogenesis in a rat model of hind limb ischemia. Antiox Redox Signal 12(9):1065–1077 Wang MJ, Cai WJ, Li N, Ding YJ, Chen Y, Zhu YC (2010) The hydrogen sulfide donor NaHS promotes angiogenesis in a rat model of hind limb ischemia. Antiox Redox Signal 12(9):1065–1077
39.
go back to reference Mccarty MF (1998) Nitric oxide deficiency, leukocyte activation, and resultant ischemia are crucial to the pathogenesis of diabetic retinopathy/ neuropathy—preventive potential of antioxidants, essential fatty acids, chromium, ginkgolides, and pentoxifylline. Med Hypotheses 50(50):435–449PubMed Mccarty MF (1998) Nitric oxide deficiency, leukocyte activation, and resultant ischemia are crucial to the pathogenesis of diabetic retinopathy/ neuropathy—preventive potential of antioxidants, essential fatty acids, chromium, ginkgolides, and pentoxifylline. Med Hypotheses 50(50):435–449PubMed
40.
go back to reference Kern TS, Yunpeng D, Miller CM, Hatala DA, Levin LA (2010) Overexpression of Bcl-2 in vascular endothelium inhibits the microvascular lesions of diabetic retinopathy. Am J Pathol 176(5):2550–2558PubMedPubMedCentral Kern TS, Yunpeng D, Miller CM, Hatala DA, Levin LA (2010) Overexpression of Bcl-2 in vascular endothelium inhibits the microvascular lesions of diabetic retinopathy. Am J Pathol 176(5):2550–2558PubMedPubMedCentral
41.
go back to reference Liu Y-Y, Nagpure BV, Wong PTH, Bian J-S (2013) Hydrogen sulfide protects SH-SY5Y neuronal cells against d-galactose induced cell injury by suppression of advanced glycation end products formation and oxidative stress. Neurochem Int 62(5):603–609PubMed Liu Y-Y, Nagpure BV, Wong PTH, Bian J-S (2013) Hydrogen sulfide protects SH-SY5Y neuronal cells against d-galactose induced cell injury by suppression of advanced glycation end products formation and oxidative stress. Neurochem Int 62(5):603–609PubMed
42.
go back to reference Oh GS, Pae HO, Lee BS, Kim BN, Kim JM, Kim HR, Jeon SB, Jeon WK, Chae HJ, Chung HT (2006) Hydrogen sulfide inhibits nitric oxide production and nuclear factor-κB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Free Rad Biol Med 41(1):106–119PubMed Oh GS, Pae HO, Lee BS, Kim BN, Kim JM, Kim HR, Jeon SB, Jeon WK, Chae HJ, Chung HT (2006) Hydrogen sulfide inhibits nitric oxide production and nuclear factor-κB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Free Rad Biol Med 41(1):106–119PubMed
43.
go back to reference Bir SC, Kolluru GK, Mccarthy P, Shen X, Pardue S, Pattillo CB, Kevil CG (2012) Hydrogen sulfide stimulates ischemic vascular remodeling through nitric oxide synthase and nitrite reduction activity regulating hypoxia-inducible factor-1α and vascular endothelial growth factor-dependent angiogenesis. J Am Heart Assoc 1(5):e004093PubMedPubMedCentral Bir SC, Kolluru GK, Mccarthy P, Shen X, Pardue S, Pattillo CB, Kevil CG (2012) Hydrogen sulfide stimulates ischemic vascular remodeling through nitric oxide synthase and nitrite reduction activity regulating hypoxia-inducible factor-1α and vascular endothelial growth factor-dependent angiogenesis. J Am Heart Assoc 1(5):e004093PubMedPubMedCentral
44.
go back to reference Liu X (2010) Hypoxia-inducible factor-1α is involved in the pro-angiogenic effect of hydrogen sulfide under hypoxic stress. Biol Pharm Bull 33(9):1550–1554PubMed Liu X (2010) Hypoxia-inducible factor-1α is involved in the pro-angiogenic effect of hydrogen sulfide under hypoxic stress. Biol Pharm Bull 33(9):1550–1554PubMed
Metadata
Title
Hydrogen sulfide serves as a biomarker in the anterior segment of patients with diabetic retinopathy
Authors
Yuyi Han
Xiaoqian Zhang
Zhiyin Zhou
Mengxi Yu
Qiuhong Wang
Jin Yao
Yi Han
Publication date
01-04-2020
Publisher
Springer Netherlands
Published in
International Ophthalmology / Issue 4/2020
Print ISSN: 0165-5701
Electronic ISSN: 1573-2630
DOI
https://doi.org/10.1007/s10792-019-01252-z

Other articles of this Issue 4/2020

International Ophthalmology 4/2020 Go to the issue