Apelin‑13 reduces high glucose‑induced mitochondrial dysfunction in cochlear hair cells by inhibiting endoplasmic reticulum stress

Huo,Zhiqiang; Gu,Jun; He,Teng

doi:10.3892/etm.2024.12515

Apelin‑13 reduces high glucose‑induced mitochondrial dysfunction in cochlear hair cells by inhibiting endoplasmic reticulum stress

Authors:
- Zhiqiang Huo
- Jun Gu
- Teng He
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Affiliations: Department of Otolaryngology, Affiliated Changshu Hospital of Nantong University, Changshu, Jiangsu 215500, P.R. China
Published online on: March 26, 2024 https://doi.org/10.3892/etm.2024.12515
Article Number: 226
Copyright: © Huo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The complex manifestation of diabetic hearing loss and the relative inaccessibility of the inner ear contribute to the lack of research. The present study aimed to reveal the role of Apelin‑13, a critical regulator of lipid metabolism, in diabetes‑induced hearing loss. Cochlear hair cells treated with high glucose (HG) were adopted as an in vitro research model, and the impacts of Apelin‑13 on cellular oxidative stress, apoptosis, mitochondrial dysfunction and endoplasmic reticulum (ER) stress were determined. In addition, cells were treated with the ER stress agonist tunicamycin to further explore its potential role in the regulatory effects of Apelin‑13. Apelin‑13 inhibited oxidative stress and apoptosis in the HG‑induced cells. Additionally, Apelin‑13 elevated mitochondrial membrane potential and ATP production, whereas it reduced mitochondrial reactive oxygen species levels. The levels of ER stress‑related proteins exhibited a downward trend in response to Apelin‑13. By contrast, tunicamycin reversed the effects of Apelin‑13 on the aforementioned aspects, suggesting the role of ER stress in the regulatory effects of Apelin‑13. In conclusion, the present study elucidated the protective role of Apelin‑13 in ameliorating HG‑induced mitochondrial functional impairment in cochlear hair cells by inhibiting ER stress.

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1	Knapp M, Tu X and Wu R: Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy. Acta Pharmacol Sin. 40:1–8. 2019.PubMed/NCBI View Article : Google Scholar
2	Avogaro A and Fadini GP: Microvascular complications in diabetes: A growing concern for cardiologists. Int J Cardiol. 291:29–35. 2019.PubMed/NCBI View Article : Google Scholar
3	Demir S, Nawroth PP, Herzig S and Ekim Üstünel B: Emerging targets in type 2 diabetes and diabetic complications. Adv Sci (Weinh). 8(e2100275)2021.PubMed/NCBI View Article : Google Scholar
4	Glessner M: American diabetes association-75th scientific sessions (June 5-9, 2015-Boston, Massachusetts, USA). Drugs Today (Barc). 51:383–386. 2015.PubMed/NCBI View Article : Google Scholar
5	Gupta S, Eavey RD, Wang M, Curhan SG and Curhan GC: Type 2 diabetes and the risk of incident hearing loss. Diabetologia. 62:281–285. 2019.PubMed/NCBI View Article : Google Scholar
6	Samocha-Bonet D, Wu B and Ryugo DK: Diabetes mellitus and hearing loss: A review. Ageing Res Rev. 71(101423)2021.PubMed/NCBI View Article : Google Scholar
7	Horikawa C, Kodama S, Tanaka S, Fujihara K, Hirasawa R, Yachi Y, Shimano H, Yamada N, Saito K and Sone H: Diabetes and risk of hearing impairment in adults: A meta-analysis. J Clin Endocrinol Metab. 98:51–58. 2013.PubMed/NCBI View Article : Google Scholar
8	Darenskaya MA, Kolesnikova LI and Kolesnikov SI: Oxidative stress: Pathogenetic role in diabetes mellitus and its complications and therapeutic approaches to correction. Bull Exp Biol Med. 171:179–189. 2021.PubMed/NCBI View Article : Google Scholar
9	Rizwan H, Pal S, Sabnam S and Pal A: High glucose augments ROS generation regulates mitochondrial dysfunction and apoptosis via stress signalling cascades in keratinocytes. Life Sci. 241(117148)2020.PubMed/NCBI View Article : Google Scholar
10	Chapman FA, Maguire JJ, Newby DE, Davenport AP and Dhaun N: Targeting the apelin system for the treatment of cardiovascular diseases. Cardiovasc Res. 119:2683–2696. 2023.PubMed/NCBI View Article : Google Scholar
11	Gao Z, Zhong X, Tan YX and Liu D: Apelin-13 alleviates diabetic nephropathy by enhancing nitric oxide production and suppressing kidney tissue fibrosis. Int J Mol Med. 48(175)2021.PubMed/NCBI View Article : Google Scholar
12	Zheng XD, Huang Y and Li H: Regulatory role of Apelin-13-mediated PI3K/AKT signaling pathway in the glucose and lipid metabolism of mouse with gestational diabetes mellitus. Immunobiology. 226(152135)2021.PubMed/NCBI View Article : Google Scholar
13	Lee SJ, Lee IK and Jeon JH: Vascular calcification-new insights into its mechanism. Int J Mol Sci. 21(2685)2020.PubMed/NCBI View Article : Google Scholar
14	Zhang P, Wang AP, Yang HP, Ai L, Zhang HJ, Wang YM, Bi YL, Fan HH, Gao J, Zhang HY and Liu JZ: Apelin-13 attenuates high glucose-induced calcification of MOVAS cells by regulating MAPKs and PI3K/AKT pathways and ROS-mediated signals. Biomed Pharmacother. 128(110271)2020.PubMed/NCBI View Article : Google Scholar
15	Khoshsirat S, Abbaszadeh HA, Peyvandi AA, Heidari F, Peyvandi M, Simani L and Niknazar S: Apelin-13 prevents apoptosis in the cochlear tissue of noise-exposed rat via Sirt-1 regulation. J Chem Neuroanat. 114(101956)2021.PubMed/NCBI View Article : Google Scholar
16	Niknazar S, Abbaszadeh HA, Peyvandi H, Rezaei O, Forooghirad H, Khoshsirat S and Peyvandi AA: Protective effect of [Pyr1]-apelin-13 on oxidative stress-induced apoptosis in hair cell-like cells derived from bone marrow mesenchymal stem cells. Eur J Pharmacol. 853:25–32. 2019.PubMed/NCBI View Article : Google Scholar
17	Xing Y, Ji Q, Li X, Ming J, Zhang N, Zha D and Lin Y: Asiaticoside protects cochlear hair cells from high glucose-induced oxidative stress via suppressing AGEs/RAGE/NF-κB pathway. Biomed Pharmacother. 86:531–536. 2017.PubMed/NCBI View Article : Google Scholar
18	Chen G, Liang X, Han Q, Mai C, Shi L, Shao Z, Hong Y, Lin F, Li M, Hu B, et al: Apelin-13 pretreatment promotes the cardioprotective effect of mesenchymal stem cells against myocardial infarction by improving their survival. Stem Cells Int. 2022(3742678)2022.PubMed/NCBI View Article : Google Scholar
19	Alizadeh Y, Jalali MM and Sehati A: Association of different severity of diabetic retinopathy and hearing loss in type 2 diabetes mellitus. Am J Otolaryngol. 43(103383)2022.PubMed/NCBI View Article : Google Scholar
20	Fettiplace R and Nam JH: Tonotopy in calcium homeostasis and vulnerability of cochlear hair cells. Hear Res. 376:11–21. 2019.PubMed/NCBI View Article : Google Scholar
21	Hudspeth AJ: Integrating the active process of hair cells with cochlear function. Nat Rev Neurosci. 15:600–614. 2014.PubMed/NCBI View Article : Google Scholar
22	Yeom J, Park J and Park JY: Fluid dynamic simulation for cellular damage due to lymphatic flow within the anatomical arrangement of the outer hair cells in the cochlea. Comput Biol Med. 161(106986)2023.PubMed/NCBI View Article : Google Scholar
23	Chen Y, Xin Y, Cheng Y and Liu X: Mitochondria-endoplasmic reticulum contacts: The promising regulators in diabetic cardiomyopathy. Oxid Med Cell Longev. 2022(2531458)2022.PubMed/NCBI View Article : Google Scholar
24	Mao H, Chen W, Chen L and Li L: Potential role of mitochondria-associated endoplasmic reticulum membrane proteins in diseases. Biochem Pharmacol. 199(115011)2022.PubMed/NCBI View Article : Google Scholar
25	Yao L, Liang X, Qiao Y, Chen B, Wang P and Liu Z: Mitochondrial dysfunction in diabetic tubulopathy. Metabolism. 131(155195)2022.PubMed/NCBI View Article : Google Scholar
26	Lyu AR, Kim TH, Shin SA, Kim EH, Yu Y, Gajbhiye A, Kwon HC, Je AR, Huh YH, Park MJ and Park YH: Hearing impairment in a mouse model of diabetes is associated with mitochondrial dysfunction, synaptopathy, and activation of the intrinsic apoptosis pathway. Int J Mol Sci. 22(8807)2021.PubMed/NCBI View Article : Google Scholar
27	Kim S, Kim S, Hwang AR, Choi HC, Lee JY and Woo CH: Apelin-13 inhibits methylglyoxal-induced unfolded protein responses and endothelial dysfunction via regulating AMPK pathway. Int J Mol Sci. 21(4069)2020.PubMed/NCBI View Article : Google Scholar
28	Zhu J, Dou S, Jiang Y, Chen J, Wang C and Cheng B: Apelin-13 protects dopaminergic neurons in MPTP-induced Parkinson's disease model mice through inhibiting endoplasmic reticulum stress and promoting autophagy. Brain Res. 1715:203–212. 2019.PubMed/NCBI View Article : Google Scholar
29	Castan-Laurell I, El Boustany R, Pereira O, Potier L, Marre M, Fumeron F, Valet P, Gourdy P, Velho G and Roussel R: Plasma apelin and risk of type 2 diabetes in a cohort from the community. Diabetes Care. 43:e15–e16. 2020.PubMed/NCBI View Article : Google Scholar
30	Dray C, Debard C, Jager J, Disse E, Daviaud D, Martin P, Attané C, Wanecq E, Guigné C, Bost F, et al: Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans. Am J Physiol Endocrinol Metab. 298:E1161–E1169. 2010.PubMed/NCBI View Article : Google Scholar
31	Fournel A, Drougard A, Duparc T, Marlin A, Brierley SM, Castro J, Le-Gonidec S, Masri B, Colom A, Lucas A, et al: Apelin targets gut contraction to control glucose metabolism via the brain. Gut. 66:258–269. 2017.PubMed/NCBI View Article : Google Scholar
32	Pope GR, Tilve S, McArdle CA, Lolait SJ and O'Carroll AM: Agonist-induced internalization and desensitization of the apelin receptor. Mol Cell Endocrinol. 437:108–119. 2016.PubMed/NCBI View Article : Google Scholar
33	Chapman FA, Nyimanu D, Maguire JJ, Davenport AP, Newby DE and Dhaun N: The therapeutic potential of apelin in kidney disease. Nat Rev Nephrol. 17:840–853. 2021.PubMed/NCBI View Article : Google Scholar
34	Read C, Nyimanu D, Williams TL, Huggins DJ, Sulentic P, Macrae RGC, Yang P, Glen RC, Maguire JJ and Davenport AP: International union of basic and clinical pharmacology. CVII. Structure and Pharmacology of the apelin receptor with a recommendation that elabela/toddler is a second endogenous peptide ligand. Pharmacol Rev. 71:467–502. 2019.PubMed/NCBI View Article : Google Scholar
35	Li C, Cheng H, Adhikari BK, Wang S, Yang N, Liu W, Sun J and Wang Y: The role of apelin-APJ system in diabetes and obesity. Front Endocrinol (Lausanne). 13(820002)2022.PubMed/NCBI View Article : Google Scholar