Long-term Inhibition of UCHL1 Decreases Hypertension and Retinopathy in Spontaneously Hypertensive Rats

Overview

Journal J Int Med Res

Publisher Sage Publications

Specialty General Medicine

Date 2021 Jun 16

PMID 34130526

Citations 1

Authors

Shasha Liu

Chengfang Wang

Jianmin Lu

Guangzheng Dai

Huixin Che

Wei He

Affiliations

Soon will be listed here.

Abstract

Objective: To investigate the role of the deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) in hypertension and retinopathy in the spontaneously hypertensive rat (SHR).

Methods: Wistar-Kyoto (WKY) rats and SHRs were administered the UCHL1 inhibitor LDN57444 (20 μg/kg/day) for 4 months. Pathological changes were detected with hematoxylin and eosin, immunofluorescence, and dihydroethidium staining. The mRNA and protein expression of UCHL1 were examined by real-time PCR and immunoblotting analysis.

Results: At 6 months of age, SHRs showed significantly increased mRNA and protein levels of UCHL1 in the retina compared with WKY rats. Moreover, SHRs exhibited significantly increased central retinal thickness, inflammation, and reactive oxygen species production compared with WKY rats, and these effects were markedly attenuated by systemic administration of the UCHL1 inhibitor LDN57444. The beneficial effects of LDN57444 were possibly associated with reduced blood pressure and the inactivation of several signaling pathways.

Conclusion: UCHL1 is involved in hypertension and retinopathy in SHRs, suggesting that UCHL1 may be used as a potential therapeutic target for treating hypertensive retinopathy.

Citing Articles

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PMID: 38538704 PMC: 10973525. DOI: 10.1038/s41598-024-57898-y.

References

Bi H, Zhang Y, Yang J, Shu Q, Yang X, Yan X . Inhibition of UCHL1 by LDN-57444 attenuates Ang II-Induced atrial fibrillation in mice. Hypertens Res. 2019; 43(3):168-177. PMC: 8075865. DOI: 10.1038/s41440-019-0354-z. View

Pohl C, Dikic I . Cellular quality control by the ubiquitin-proteasome system and autophagy. Science. 2019; 366(6467):818-822. DOI: 10.1126/science.aax3769. View

Wong T, Wong T, Mitchell P . The eye in hypertension. Lancet. 2007; 369(9559):425-35. DOI: 10.1016/S0140-6736(07)60198-6. View

Herrmann H, Fiedler U, Blodner R . Pathogenesis of myocardial fibrosis in spontaneously hypertensive rats (SHR). Eur Heart J. 1995; 16(2):243-52. DOI: 10.1093/oxfordjournals.eurheartj.a060891. View

Ying X, Zhao Y, Yao T, Yuan A, Xu L, Gao L . Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling. Hypertension. 2016; 68(5):1160-1170. DOI: 10.1161/HYPERTENSIONAHA.116.07562. View

Ramos C, Lin C, Liu X, Antonetti D . The EPAC-Rap1 pathway prevents and reverses cytokine-induced retinal vascular permeability. J Biol Chem. 2017; 293(2):717-730. PMC: 5767874. DOI: 10.1074/jbc.M117.815381. View

Yu X, Zhang D, Jia L, Qi J, Song X, Tan H . Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress. Toxicol Appl Pharmacol. 2015; 284(3):315-22. DOI: 10.1016/j.taap.2015.02.023. View

Robinson R, Ho C, Tan Q, Luu C, Moe K, Cheung C . Fluvastatin downregulates VEGF-A expression in TNF-α-induced retinal vessel tortuosity. Invest Ophthalmol Vis Sci. 2011; 52(10):7423-31. DOI: 10.1167/iovs.11-7912. View

Nakashima R, Goto Y, Koyasu S, Kobayashi M, Morinibu A, Yoshimura M . UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization. Sci Rep. 2017; 7(1):6879. PMC: 5537219. DOI: 10.1038/s41598-017-06605-1. View

10.

Kobayashi E, Aga M, Kondo S, Whitehurst C, Yoshizaki T, Pagano J . C-Terminal Farnesylation of UCH-L1 Plays a Role in Transport of Epstein-Barr Virus Primary Oncoprotein LMP1 to Exosomes. mSphere. 2018; 3(1). PMC: 5806207. DOI: 10.1128/mSphere.00030-18. View

11.

Zhou T, Rivera J, Bhosle V, Lahaie I, Shao Z, Tahiri H . Choroidal Involution Is Associated with a Progressive Degeneration of the Outer Retinal Function in a Model of Retinopathy of Prematurity: Early Role for IL-1β. Am J Pathol. 2016; 186(12):3100-3116. DOI: 10.1016/j.ajpath.2016.08.004. View

12.

Graham S, Liu H . Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia. Ageing Res Rev. 2016; 34:30-38. PMC: 5250550. DOI: 10.1016/j.arr.2016.09.011. View

13.

Gao H, Hartnett S, Li Y . Ubiquitin C-Terminal Hydrolase L1 regulates myoblast proliferation and differentiation. Biochem Biophys Res Commun. 2017; 492(1):96-102. PMC: 5584584. DOI: 10.1016/j.bbrc.2017.08.027. View

14.

Shruthi K, Reddy S, Reddy G . Ubiquitin-proteasome system and ER stress in the retina of diabetic rats. Arch Biochem Biophys. 2017; 627:10-20. DOI: 10.1016/j.abb.2017.06.006. View

15.

Han X, Zhang Y, Fu T, Li P, Cong T, Li H . Blockage of UCHL1 activity attenuates cardiac remodeling in spontaneously hypertensive rats. Hypertens Res. 2020; 43(10):1089-1098. DOI: 10.1038/s41440-020-0486-1. View

16.

Yue J, Zhao X . GPR174 suppression attenuates retinopathy in angiotensin II (Ang II)-treated mice by reducing inflammation via PI3K/AKT signaling. Biomed Pharmacother. 2020; 122:109701. DOI: 10.1016/j.biopha.2019.109701. View

17.

Zhang Y, Geng C, Yang J, Fang J, Yan X, Li P . Chronic inhibition of chemokine receptor CXCR2 attenuates cardiac remodeling and dysfunction in spontaneously hypertensive rats. Biochim Biophys Acta Mol Basis Dis. 2019; 1865(12):165551. DOI: 10.1016/j.bbadis.2019.165551. View

18.

Katsi V, Marketou M, Vlachopoulos C, Tousoulis D, Souretis G, Papageorgiou N . Impact of arterial hypertension on the eye. Curr Hypertens Rep. 2012; 14(6):581-90. DOI: 10.1007/s11906-012-0283-6. View

19.

Wang S, Li J, Wang T, Bai J, Zhang Y, Lin Q . Ablation of Immunoproteasome β5i Subunit Suppresses Hypertensive Retinopathy by Blocking ATRAP Degradation in Mice. Mol Ther. 2019; 28(1):279-292. PMC: 6953897. DOI: 10.1016/j.ymthe.2019.09.025. View

20.

Poon W, Carlos A, Aguilar B, Berchtold N, Kawano C, Zograbyan V . β-Amyloid (Aβ) oligomers impair brain-derived neurotrophic factor retrograde trafficking by down-regulating ubiquitin C-terminal hydrolase, UCH-L1. J Biol Chem. 2013; 288(23):16937-16948. PMC: 3675626. DOI: 10.1074/jbc.M113.463711. View