Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Ophthalmology
Published in: BMC Ophthalmology 1/2020

Open Access 01-12-2020 | Pigmentary Retinopathy | Research article

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Authors: Weiming Yan, Pan Long, Dongyu Wei, Weihua Yan, Xiangrong Zheng, Guocang Chen, Jiancong Wang, Zuoming Zhang, Tao Chen, Meizhu Chen

Published in: BMC Ophthalmology | Issue 1/2020

Login to get access

Abstract

Background

Retinitis pigmentosa (RP) is a kind of inherited retinal degenerative diseases characterized by the progressive loss of photoreceptors. RP has been a conundrum without satisfactory countermeasures in clinic until now. Acetaldehyde dehydrogenase 2 (ALDH2), a major enzyme involved in aldehyde detoxification, has been demonstrated to be beneficial for a growing number of human diseases, such as cardiovascular dysfunction, diabetes mellitus and neurodegeneration. However, its protective effect against RP remains unknown. Our study explored the impact of ALDH2 on retinal function and structure in N-methyl-N-nitrosourea (MNU)-induced RP rats.

Methods

Rats were gavaged with 5 mg/kg Alda-1, an ALDH2 agonist, 5 days before and 3 days after MNU administration. Assessments of retinal function and morphology as well as measurement of specific proteins expression level were conducted.

Results

Electroretinogram recordings showed that Alda-1 administration alleviated the decrease in amplitude caused by MNU, rendering protection of retinal function. Mitigation of photoreceptor degeneration in MNU-treated retinas was observed by optical coherence tomography and retinal histological examination. In addition, Western blotting results revealed that ALDH2 protein expression level was upregulatedwith increased expression of SIRT1 protein after the Alda-1 intervention. Besides, endoplasmic reticulum stress (ERS) was reduced according to the significant downregulation of GRP78 protein, while apoptosis was ameliorated as shown by the decreased expression of PARP1 protein.

Conclusions

Together, our data demonstrated that ALDH2 could provide preservation of retinal function and morphology against MNU-induced RP, with the underlying mechanism at least partly related to the modulation of SIRT1, ERS and apoptosis.
Literature
1.
Kelbsch C, Maeda F, Lisowska J, et al. Analysis of retinal function using chromatic pupillography in retinitis pigmentosa and the relationship to electrically evoked phosphene thresholds[J]. Acta Ophthalmol. 2017;95(4):e261–9.PubMedCrossRef
2.
Dias MF, Joo K, Kemp JA, et al. Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives[J]. Prog Retin Eye Res. 2018;63:107–31.PubMedCrossRef
3.
Martin-Merida I, Sanchez-Alcudia R, Fernandez-San JP, et al. Analysis of the PRPF31 gene in Spanish autosomal dominant retinitis Pigmentosa patients: a novel genomic rearrangement[J]. Invest Ophthalmol Vis Sci. 2017;58(2):1045–53.PubMedCrossRef
4.
Fischer MD, Mcclements ME, Martinez-Fernandez DLCC, et al. Codon-optimized RPGR improves stability and efficacy of AAV8 gene therapy in two mouse models of X-linked retinitis Pigmentosa[J]. Mol Ther. 2017;25(8):1854–65.PubMedPubMedCentralCrossRef
5.
Oner A, Gonen ZB, Sinim N, et al. Subretinal adipose tissue-derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: a phase I clinical safety study[J]. Stem Cell Res Ther. 2016;7(1):178.PubMedPubMedCentralCrossRef
6.
7.
Edenberg HJ, Mcclintick JN. Alcohol dehydrogenases, aldehyde dehydrogenases and alcohol use disorders: a critical review[J]. Alcohol Clin Exp Res. 2018.
8.
Deza-Ponzio R, Herrera ML, Bellini MJ, et al. Aldehyde dehydrogenase 2 in the spotlight: the link between mitochondria and neurodegeneration[J]. Neurotoxicology. 2018;68:19–24.PubMedCrossRef
9.
Wang S, Wang C, Turdi S, et al. ALDH2 protects against high fat diet-induced obesity cardiomyopathy and defective autophagy: role of CaM kinase II, histone H3K9 methyltransferase SUV39H, Sirt1, and PGC-1alpha deacetylation[J]. Int J Obes. 2018;42(5):1073–87.CrossRef
10.
Yang MY, Wang YB, Han B, et al. Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells[J]. Acta Pharmacol Sin. 2018;39(1):48–58.PubMedCrossRef
11.
Yu Y, Jia XJ, Zhang WP, et al. The protective effect of low-dose ethanol on myocardial fibrosis through Downregulating the JNK signaling pathway in diabetic rats[J]. J Diabetes Res. 2016;2016:3834283.PubMedPubMedCentral
12.
Velez G, Machlab DA, Tang PH, et al. Proteomic analysis of the human retina reveals region-specific susceptibilities to metabolic- and oxidative stress-related diseases[J]. PLoS One. 2018;13(2):e193250.CrossRef
13.
Campbell LJ, West MC, Jensen AM. A high content, small molecule screen identifies candidate molecular pathways that regulate rod photoreceptor outer segment renewal[J]. Sci Rep. 2018;8(1):14017.PubMedPubMedCentralCrossRef
14.
15.
Cronin T, Raffelsberger W, Lee-Rivera I, et al. The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress[J]. Cell Death Differ. 2010;17(7):1199–210.PubMedCrossRef
16.
Giordano CR, Roberts R, Krentz KA, et al. Catalase therapy corrects oxidative stress-induced pathophysiology in incipient diabetic retinopathy[J]. Invest Ophthalmol Vis Sci. 2015;56(5):3095–102.PubMedPubMedCentralCrossRef
17.
Krilis M, Qi M, Qi J, et al. Dual roles of different redox forms of complement factor H in protecting against age related macular degeneration[J]. Free Radic Biol Med. 2018;129:237–46.PubMedCrossRef
18.
Mcdowell RE, Mcgeown JG, Stitt AW, et al. Therapeutic potential of targeting lipid aldehydes and lipoxidation end-products in the treatment of ocular disease[J]. Future Med Chem. 2013;5(2):189–211.PubMedCrossRef
19.
He M, Long P, Yan W, et al. ALDH2 attenuates early-stage STZ-induced aged diabetic rats retinas damage via Sirt1/Nrf2 pathway[J]. Life Sci. 2018;215:227–35.PubMedCrossRef
20.
Beretta M, Gorren AC, Wenzl MV, et al. Characterization of the east Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1[J]. J Biol Chem. 2010;285(2):943–52.PubMedCrossRef
21.
Yan W, Yao L, Liu W, et al. A kind of rd1 mouse in C57BL/6J mice from crossing with a mutated Kunming mouse[J]. Gene. 2017;607:9–15.PubMedCrossRef
22.
Mcculloch DL, Marmor MF, Brigell MG, et al. ISCEV standard for full-field clinical electroretinography (2015 update)[J]. Doc Ophthalmol. 2015;130(1):1–12.PubMedCrossRef
23.
Yan W, Long P, Chen T, et al. A natural occurring mouse model with Adgrv1 mutation of usher syndrome 2C and characterization of its recombinant inbred strains[J]. Cell Physiol Biochem. 2018;47(5):1883–97.PubMedCrossRef
24.
Reisenhofer MH, Balmer JM, Enzmann V. What can pharmacological models of retinal degeneration tell us?[J]. Curr Mol Med. 2017;17(2):100–7.PubMedCrossRef
25.
Kiuchi K, Kondo M, Ueno S, et al. Functional rescue of N-methyl-N-nitrosourea-induced retinopathy by nicotinamide in Sprague-Dawley rats[J]. Curr Eye Res. 2003;26(6):355–62.PubMedCrossRef
26.
Yuge K, Nambu H, Senzaki H, et al. N-methyl-N-nitrosourea-induced photoreceptor apoptosis in the mouse retina[J]. In Vivo. 1996;10(5):483–8.PubMed
27.
Kakiuchi D, Taketa Y, Ohta E, et al. Combination of circulating microRNAs as indicators of specific targets of retinal toxicity in rats[J]. Toxicol. 2018.
28.
Jeong E, Paik SS, Jung SW, et al. Morphological and functional evaluation of an animal model for the retinal degeneration induced by N-methyl-N-nitrosourea[J]. Anat Cell Biol. 2011;44(4):314–23.PubMedPubMedCentralCrossRef
29.
Oyama T, Isse T, Kagawa N, et al. Tissue-distribution of aldehyde dehydrogenase 2 and effects of the ALDH2 gene-disruption on the expression of enzymes involved in alcohol metabolism[J]. Front Biosci. 2005;10:951–60.PubMedCrossRef
30.
Mcdowell RE, Mcgahon MK, Augustine J, et al. Diabetes impairs the aldehyde detoxifying capacity of the retina[J]. Invest Ophthalmol Vis Sci. 2016;57(11):4762–71.PubMedCrossRef
31.
Galbis-Estrada C, Pons-Vazquez S, Gallego-Pinazo R, et al. Glutathione-dependent formaldehyde dehydrogenase (ADH3) and low km mitochondrial aldehyde dehydrogenase (ALDH2). New evidence for differential expression in the rat retina in response to oxidative stress[J]. Free Radic Res. 2012;46(1):77–84.PubMedCrossRef
32.
Campochiaro PA, Mir TA. The mechanism of cone cell death in retinitis Pigmentosa[J]. Prog Retin Eye Res. 2018;62:24–37.PubMedCrossRef
33.
Tao Y, Chen T, Liu ZY, et al. Topographic quantification of the Transcorneal electrical stimulation (TES)-induced protective effects on N-methyl-N-Nitrosourea-treated retinas[J]. Invest Ophthalmol Vis Sci. 2016;57(11):4614–24.PubMedCrossRef
34.
Boudard DL, Tanimoto N, Huber G, et al. Cone loss is delayed relative to rod loss during induced retinal degeneration in the diurnal cone-rich rodent Arvicanthis ansorgei[J]. Neurosci. 2010;169(4):1815–30.CrossRef
35.
van der Meer FJ, Faber DJ, Aalders MC, et al. Apoptosis- and necrosis-induced changes in light attenuation measured by optica coherence tomography[J]. Lasers Med Sci. 2010;25(2):259–67.PubMedCrossRef
36.
de Bruin DM, Broekgaarden M, van Gemert MJ, et al. Assesment of apoptosis induced changes in scattering using optical coherence tomography[J]. J Biophotonics. 2016;9(9):913–23.PubMedCrossRef
37.
Aziz MK, Ni A, Esserman DA, et al. Evidence of early ultrastructural photoreceptor abnormalities in light-induced retinal degeneration using spectral domain optical coherence tomography[J]. Br J Ophthalmol. 2014;98(7):984–9.PubMedCrossRef
38.
Pennesi ME, Michaels KV, Magee SS, et al. Long-term characterization of retinal degeneration in rd1 and rd10 mice using spectral domain optical coherence tomography[J]. Invest Ophthalmol Vis Sci. 2012;53(8):4644–56.PubMedPubMedCentralCrossRef
39.
Li JH, Ju GX, Jiang JL, et al. Lipoic acid protects gastric mucosa from ethanol-induced injury in rat through a mechanism involving aldehyde dehydrogenase 2 activation[J]. Alcohol. 2016;56:21–8.PubMedCrossRef
40.
Mittal M, Pal S, China SP, et al. Pharmacological activation of aldehyde dehydrogenase 2 promotes osteoblast differentiation via bone morphogenetic protein-2 and induces bone anabolic effect[J]. Toxicol Appl Pharmacol. 2017;316:63–73.PubMedCrossRef
41.
Wong P. Apoptosis, retinitis pigmentosa, and degeneration[J]. Biochem Cell Biol. 1994;72(11–12):489–98.PubMedCrossRef
42.
Gill SJ, Travers J, Pshenichnaya I, et al. Combinations of PARP inhibitors with Temozolomide drive PARP1 trapping and apoptosis in Ewing's sarcoma[J]. PLoS One. 2015;10(10):e140988.CrossRef
43.
Choudhury S, Bhootada Y, Gorbatyuk O, et al. Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal degeneration[J]. Cell Death Dis. 2013;4:e528.PubMedPubMedCentralCrossRef
44.
Sancho-Pelluz J, Paquet-Durand F. HDAC inhibition prevents Rd1 mouse photoreceptor degeneration[J]. Adv Exp Med Biol. 2012;723:107–13.PubMedCrossRef
45.
Wang Y, He J, Liao M, et al. An overview of Sirtuins as potential therapeutic target: structure, function and modulators[J]. Eur J Med Chem. 2019;161:48–77.PubMedCrossRef
46.
Zhou M, Luo J, Zhang H. Role of Sirtuin 1 in the pathogenesis of ocular disease (review)[J]. Int J Mol Med. 2018;42(1):13–20.PubMed
47.
Jaliffa C, Ameqrane I, Dansault A, et al. Sirt1 involvement in rd10 mouse retinal degeneration[J]. Invest Ophthalmol Vis Sci. 2009;50(8):3562–72.PubMedCrossRef
48.
Qi LS, Yao L, Liu W, et al. Sirtuin type 1 mediates the retinal protective effect of hydrogen-rich saline against light-induced damage in rats[J]. Invest Ophthalmol Vis Sci. 2015;56(13):8268–79.PubMedCrossRef
49.
Yan WM, Chen T, Wang XC, et al. The reason for the amelioration of N-methyl-N-nitrosourea-induced retinitis pigmentosa in rats by hydrogen-rich saline[J]. Int J Ophthalmol. 2017;10(10):1495–503.PubMedPubMedCentral
50.
Xue L, Yang F, Han Z, et al. ALDH2 mediates the dose-response protection of chronic ethanol against endothelial senescence through SIRT1/p53 pathway[J]. Biochem Biophys Res Commun. 2018;504(4):777–83.PubMedCrossRef
51.
Li C, Sun W, Gu C, et al. Targeting ALDH2 for therapeutic interventions in chronic pain-related myocardial ischemic susceptibility[J]. Theranostics. 2018;8(4):1027–41.PubMedPubMedCentralCrossRef
52.
Peters JC, Bhattacharya S, Clark AF, et al. Increased endoplasmic reticulum stress in human glaucomatous trabecular meshwork cells and tissues[J]. Invest Ophthalmol Vis Sci. 2015;56(6):3860–8.PubMedPubMedCentralCrossRef
53.
Lenin R, Nagy PG, Alli S, et al. Critical role of endoplasmic reticulum stress in chronic endothelial activation-induced visual deficits in tie2-tumor necrosis factor mice[J]. J Cell Biochem. 2018;119(10):8460–71.PubMedPubMedCentralCrossRef
54.
Minasyan L, Sreekumar PG, Hinton DR, et al. Protective mechanisms of the mitochondrial-derived peptide Humanin in oxidative and endoplasmic reticulum stress in RPE cells[J]. Oxidative Med Cell Longev. 2017;2017:1675230.CrossRef
55.
56.
Tsai YL, Ha DP, Zhao H, et al. Endoplasmic reticulum stress activates SRC, relocating chaperones to the cell surface where GRP78/CD109 blocks TGF-beta signaling[J]. Proc Natl Acad Sci U S A. 2018;115(18):E4245–54.PubMedPubMedCentralCrossRef
57.
Reisenhofer M, Balmer J, Zulliger R, et al. Multiple programmed cell death pathways are involved in N-methyl-N-nitrosourea-induced photoreceptor degeneration[J]. Graefes Arch Clin Exp Ophthalmol. 2015;253(5):721–31.PubMedCrossRef
58.
Zhong W, Zhang W, Li Q, et al. Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice[J]. J Hepatol. 2015;62(6):1375–81.PubMedCrossRef
59.
Li SY, Gilbert SA, Li Q, et al. Aldehyde dehydrogenase-2 (ALDH2) ameliorates chronic alcohol ingestion-induced myocardial insulin resistance and endoplasmic reticulum stress[J]. J Mol Cell Cardiol. 2009;47(2):247–55.PubMedPubMedCentralCrossRef
60.
Kassan M, Vikram A, Kim YR, et al. Sirtuin1 protects endothelial Caveolin-1 expression and preserves endothelial function via suppressing miR-204 and endoplasmic reticulum stress[J]. Sci Rep. 2017;7:42265.PubMedPubMedCentralCrossRef
61.
Zheng X, Xu F, Liang H, et al. SIRT1/HSF1/HSP pathway is essential for exenatide-alleviated, lipid-induced hepatic endoplasmic reticulum stress[J]. Hepatol. 2017;66(3):809–24.CrossRef
62.
Kang X, Yang W, Wang R, et al. Sirtuin-1 (SIRT1) stimulates growth-plate chondrogenesis by attenuating the PERK-eIF-2alpha-CHOP pathway in the unfolded protein response[J]. J Biol Chem. 2018;293(22):8614–25.PubMedPubMedCentralCrossRef
Metadata
Title
Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study
Authors
Weiming Yan
Pan Long
Dongyu Wei
Weihua Yan
Xiangrong Zheng
Guocang Chen
Jiancong Wang
Zuoming Zhang
Tao Chen
Meizhu Chen
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Ophthalmology / Issue 1/2020
Electronic ISSN: 1471-2415
DOI
https://doi.org/10.1186/s12886-020-1330-8

Other articles of this Issue 1/2020

BMC Ophthalmology 1/2020 Go to the issue

Case report

Post-operative optical coherence tomography angiography features of chorioretinal folds resulting from pleomorphic adenoma of the lacrimal gland (PALG) of orbit- a case report

Research article

Systematic review of the incidence of post-operative trichiasis in Africa

Case report

Scleral thinning surgery for bullous retinal detachment with retinal pigment epithelial tear in central serous chorioretinopathy: a case report

Case report

Post-intravitreal injection endophthalmitis secondary to Turicella otitidis: a case report

Research article

Systemic and ocular diseases associated with the development of diabetic macular edema among Japanese patients with diabetes mellitus

Research article

Influence of pupil dilation on the Barrett universal II (new generation), Haigis (4th generation), and SRK/T (3rd generation) intraocular lens calculation formulas: a retrospective study