{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:18:46Z","timestamp":1781666326291,"version":"3.54.5"},"reference-count":49,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T00:00:00Z","timestamp":1697673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Osaka Eye Bank Association Fund (Osaka, Japan)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>This study aimed to determine the role of oxidative stress produced by the renin\u2013angiotensin system (RAS) in cataract formation in streptozotocin-induced diabetic rats (STZ) using angiotensin II receptor blockers (ARBs). Rats were treated with streptozotocin and orally administered candesartan (2.5 mg\/kg\/day) or a normal diet for 10 weeks until sacrifice. Cataract progression was assessed through a slit-lamp examination. Animals were euthanized at 18 weeks, and the degree of cataract progression was evaluated. Oxidative stress was also assessed. In STZ-treated rats, lens opacity occurred at 12 weeks. Cataract progression was inhibited in the ARB-treated group compared with the placebo group (p &lt; 0.05). STZ-treated rats exhibited upregulated angiotensin-converting enzyme (ACE) gene expression than control rats. Oxidative stress-related factors were upregulated in the placebo-treated group but suppressed in the ARB-treated group. A correlation coefficient test revealed a positive correlation between ACE gene expression and oxidative stress-related factors and a negative correlation between ACE and superoxide dismutase. Immunostaining revealed oxidative stress-related factors and advanced glycation end products in the lens cortex of the placebo-treated group. The mechanism of diabetic cataracts may be related to RAS, and the increase in focal ACE and angiotensin II in the lens promotes oxidative stress-related factor production.<\/jats:p>","DOI":"10.3390\/jcm12206627","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T11:46:26Z","timestamp":1697715986000},"page":"6627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Effects of Angiotensin Receptor Blockers on Streptozotocin-Induced Diabetic Cataracts"],"prefix":"10.3390","volume":"12","author":[{"given":"Gaku","family":"Ishigooka","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shou","family":"Oosuka","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-8168","authenticated-orcid":false,"given":"Denan","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Innovative Medicine, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-4477","authenticated-orcid":false,"given":"Shinji","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Innovative Medicine, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3074-162X","authenticated-orcid":false,"given":"Teruyo","family":"Kida","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e3073","DOI":"10.1002\/dmrr.3073","article-title":"A systematic review of risk factors for cataract in type 2 diabetes","volume":"35","author":"Drinkwater","year":"2019","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s11892-021-01418-z","article-title":"Cataract Surgery Considerations for Diabetic Patients","volume":"21","author":"Go","year":"2021","journal-title":"Curr. Diab. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"608751","DOI":"10.1155\/2010\/608751","article-title":"Diabetic cataract-pathogenesis, epidemiology and treatment","volume":"2010","author":"Pollreisz","year":"2010","journal-title":"J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.exer.2008.08.001","article-title":"Synergistic effect of osmotic and oxidative stress in slow-developing cataract formation","volume":"87","author":"Chan","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.jdiacomp.2012.04.005","article-title":"Osmotic stress induced oxidative damage: Possible mechanism of cataract formation in diabetes","volume":"26","author":"Hashim","year":"2012","journal-title":"J. Diabetes Complicat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1096\/fasebj.13.1.23","article-title":"Contributions of polyol pathway to oxidative stress in diabetic cataract","volume":"13","author":"Lee","year":"1999","journal-title":"FASEB J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1007\/s12011-018-1373-3","article-title":"Zinc Supplementation Ameliorates Diabetic Cataract Through Modulation of Crystallin Proteins and Polyol Pathway in Experimental Rats","volume":"187","author":"Barman","year":"2019","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.4103\/ijo.IJO_1784_22","article-title":"Enzymatic and biochemical properties of lens in age-related cataract versus diabetic cataract: A narrative review","volume":"71","author":"Mishra","year":"2023","journal-title":"Indian J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chen, Y.Y., Wu, T.T., Ho, C.Y., Yeh, T.C., Sun, G.C., Kung, Y.H., Wong, T.Y., Tseng, C.J., and Cheng, P.W. (2019). Dapagliflozin Prevents NOX- and SGLT2-Dependent Oxidative Stress in Lens Cells Exposed to Fructose-Induced Diabetes Mellitus. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184357"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Abdul Nasir, N.A., Agarwal, R., Sheikh Abdul Kadir, S.H., Vasudevan, S., Tripathy, M., Iezhitsa, I., Mohammad Daher, A., Ibrahim, M.I., and Mohd Ismail, N. (2017). Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174542"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14684","DOI":"10.1038\/s41598-019-51059-2","article-title":"Vitamin K1 prevents diabetic cataract by inhibiting lens aldose reductase 2 (ALR2) activity","volume":"9","author":"Thiagarajan","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lim, J.C., Caballero Arredondo, M., Braakhuis, A.J., and Donaldson, P.J. (2020). Vitamin C and the Lens: New Insights into Delaying the Onset of Cataract. Nutrients, 12.","DOI":"10.3390\/nu12103142"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1080\/02713680802389851","article-title":"Involvement of angiotensin II-dependent vascular endothelial growth factor gene expression via NADPH oxidase in the retina in a type 2 diabetic rat model","volume":"33","author":"Fukumoto","year":"2008","journal-title":"Curr. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"28","DOI":"10.2174\/1874364101509010028","article-title":"Angiotensin(1-7) and ACE2, \u201cThe Hot Spots\u201d of Renin-Angiotensin System, Detected in the Human Aqueous Humor","volume":"9","author":"Holappa","year":"2015","journal-title":"Open Ophthalmol. J."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Choudhary, R., Shree, J., Singh, A., and Bodakhe, S.H. (2021). Role of the renin\u2013angiotensin system in the development of cataract formation in angiotensin-II-induced experimental rats. J. Biochem. Mol. Toxicol., 35.","DOI":"10.1002\/jbt.22789"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Shree, J., Choudhary, R., and Bodakhe, S.H. (2019). Losartan delays the progression of streptozotocin-induced diabetic cataracts in albino rats. J. Biochem. Mol. Toxicol., 33.","DOI":"10.1002\/jbt.22342"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3317\/jraas.2005.003","article-title":"The DIabetic REtinopathy Candesartan Trials (DIRECT) Programme: Baseline characteristics","volume":"6","author":"Sjolie","year":"2005","journal-title":"J. Renin Angiotensin Aldosterone Syst."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1001\/jama.2022.19590","article-title":"Treatment of Hypertension: A Review","volume":"328","author":"Carey","year":"2022","journal-title":"JAMA"},{"key":"ref_20","unstructured":"(2023, August 18). ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Available online: https:\/\/www.arvo.org\/About\/policies\/arvo-statement-for-the-use-of-animals-in-ophthalmic-and-vision-research\/."},{"key":"ref_21","first-page":"263","article-title":"Immunohistochemistry of angiotensin I-converting enzyme in rat eye structures involved in aqueous humor regulation","volume":"59","author":"Laliberte","year":"1988","journal-title":"Lab. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kang, Q., and Yang, C. (2020). Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol., 37.","DOI":"10.1016\/j.redox.2020.101799"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41419-017-0135-z","article-title":"Cellular death, reactive oxygen species (ROS) and diabetic complications","volume":"9","author":"Volpe","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.preteyeres.2007.01.004","article-title":"Nitric oxide: Ocular blood flow, glaucoma, and diabetic retinopathy","volume":"26","author":"Toda","year":"2007","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1038\/s41598-021-81482-3","article-title":"Hyperglycemia-induced VEGF and ROS production in retinal cells is inhibited by the mTOR inhibitor, rapamycin","volume":"11","author":"Kida","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/S0021-5155(02)00624-X","article-title":"Renin-angiotensin system in proliferative diabetic retinopathy and its gene expression in cultured human muller cells","volume":"47","author":"Kida","year":"2003","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.peptides.2012.04.008","article-title":"The retinal renin-angiotensin system: Roles of angiotensin II and aldosterone","volume":"36","author":"Agrotis","year":"2012","journal-title":"Peptides"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/jdi.12842","article-title":"(Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy","volume":"10","author":"Kanda","year":"2019","journal-title":"J. Diabetes Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S2213-8587(14)70256-6","article-title":"Effects of RAS inhibitors on diabetic retinopathy: A systematic review and meta-analysis","volume":"3","author":"Wang","year":"2015","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1016\/S0140-6736(08)61412-9","article-title":"Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: Randomised, placebo-controlled trials","volume":"372","author":"Chaturvedi","year":"2008","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3109\/02713681003664923","article-title":"Reduction of Inducible Nitric Oxide Synthase via Angiotensin Receptor Blocker Prevents the Oxidative Retinal Damage in Diabetic Hypertensive Rats","volume":"35","author":"Silva","year":"2010","journal-title":"Curr. Eye Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.lfs.2016.10.012","article-title":"Olmesartan, an angiotensin II receptor blocker inhibits the progression of cataract formation in cadmium chloride induced hypertensive albino rats","volume":"167","author":"Choudhary","year":"2016","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3109\/02713680903484242","article-title":"Plasma and aqueous humor angiotensin-converting enzyme levels in patients with diabetic retinopathy","volume":"35","author":"Aydin","year":"2010","journal-title":"Curr. Eye Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Umran, N.S.S., Mohamed, S., Lau, S.F., and Mohd Ishak, N.I. (2020). Citrus hystrix leaf extract attenuated diabetic-cataract in STZ-rats. J. Food Biochem., 44.","DOI":"10.1111\/jfbc.13258"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1177\/1535370215627031","article-title":"Featured Article: Inhibition of diabetic cataract by glucose tolerance factor extracted from yeast","volume":"241","author":"Mirsky","year":"2016","journal-title":"Exp. Biol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zhang, X., Peng, L., Dai, Y., Xie, Q., Wu, P., Chen, M., and Liu, C. (2021). Anti-cataract effects of coconut water in vivo and in vitro. Biomed. Pharmacother., 143.","DOI":"10.1016\/j.biopha.2021.112032"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1248\/bpb.b18-00328","article-title":"Anti-cataract Effect of Resveratrol in High-Glucose-Treated Streptozotocin-Induced Diabetic Rats","volume":"41","author":"Higashi","year":"2018","journal-title":"Biol. Pharm. Bull."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1080\/14786419.2017.1333991","article-title":"Delaying of cataract through intervention of Hemidesmus indicus in STZ induced diabetic rats","volume":"32","author":"Tirumani","year":"2018","journal-title":"Nat. Prod. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1124\/pr.112.007278","article-title":"A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists","volume":"65","author":"Michel","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2356507","DOI":"10.1155\/2022\/2356507","article-title":"Candesartan Reduces Neuronal Apoptosis Caused by Ischemic Stroke via Regulating the FFAR1\/ITGA4 Pathway","volume":"2022","author":"Ding","year":"2022","journal-title":"Mediat. Inflamm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1038\/s12276-023-00982-6","article-title":"Candesartan, an angiotensin-II receptor blocker, ameliorates insulin resistance and hepatosteatosis by reducing intracellular calcium overload and lipid accumulation","volume":"55","author":"Lee","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.pbiomolbio.2014.05.002","article-title":"The \u03b2\u03b3-crystallins: Native state stability and pathways to aggregation","volume":"115","author":"Serebryany","year":"2014","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"887","DOI":"10.2174\/156652409789105598","article-title":"Effects of alpha-crystallin on lens cell function and cataract pathology","volume":"9","author":"Andley","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1016\/j.ijbiomac.2019.04.037","article-title":"Prevention of alpha-crystallin glycation and aggregation using l-lysine results in the inhibition of in vitro catalase heat-induced-aggregation and suppression of cataract formation in the diabetic rat","volume":"132","author":"Bahmani","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bahmani, F., Bathaie, S.Z., Aldavood, S.J., and Ghahghaei, A. (2016). Inhibitory Effect of Crocin(s) on Lens alpha-Crystallin Glycation and Aggregation, Results in the Decrease of the Risk of Diabetic Cataract. Molecules, 21.","DOI":"10.3390\/molecules21020143"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.jnutbio.2008.05.015","article-title":"Delay of diabetic cataract in rats by the antiglycating potential of cumin through modulation of alpha-crystallin chaperone activity","volume":"20","author":"Kumar","year":"2009","journal-title":"J. Nutr. Biochem."},{"key":"ref_47","first-page":"561","article-title":"Modulation of alpha-crystallin chaperone activity in diabetic rat lens by curcumin","volume":"11","author":"Kumar","year":"2005","journal-title":"Mol. Vis."},{"key":"ref_48","first-page":"91","article-title":"Relationship between the Structure and Chaperone Activity of Human alphaA-Crystallin after Its Modification with Diabetes-Associated Oxidative Agents and Protective Role of Antioxidant Compounds","volume":"87","author":"Moghadam","year":"2022","journal-title":"Biochemistry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s00417-010-1313-1","article-title":"Lens epithelial cell apoptosis initiates diabetic cataractogenesis in the Zucker diabetic fatty rat","volume":"248","author":"Kim","year":"2010","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/20\/6627\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:09:57Z","timestamp":1760130597000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/20\/6627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,19]]},"references-count":49,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["jcm12206627"],"URL":"https:\/\/doi.org\/10.3390\/jcm12206627","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,19]]}}}