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  3. Hyperglycemia induces tear reduction and dry eye in diabetic mice through the norepinephrine-α1AR -mitochondrial impairment axis of lacrimal gland

Hyperglycemia induces tear reduction and dry eye in diabetic mice through the norepinephrine-α1AR -mitochondrial impairment axis of lacrimal gland

  • Am J Pathol. 2023 Apr 21;S0002-9440(23)00132-3. doi: 10.1016/j.ajpath.2023.03.015.
Sai Zhang 1,  Qun Wang 2,  Mingli Qu 1,  Qing Chen 3,  Xiaofei Bai 2,  Zhenzhen Zhang 4,  Qingjun Zhou 5,  Lixin Xie 6
Affiliations

Affiliations

  • 1 Shandong First Medical University, Jinan, 250021, China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute of Shandong First Medical University, Qingdao, 266071, China.
  • 2 State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute of Shandong First Medical University, Qingdao, 266071, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, China.
  • 3 School of Clinical Medicine, Weifang Medical University, Weifang, 261053, China.
  • 4 Medical College of Qingdao University, Qingdao, 266071, China.
  • 5 State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute of Shandong First Medical University, Qingdao, 266071, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, China. Electronic address: zhouqingjun@sdfmu.edu.cn.
  • 6 State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute of Shandong First Medical University, Qingdao, 266071, China; Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, China. Electronic address: lxxie@sdfmu.edu.cn.
PMID: 37088455 DOI: 10.1016/j.ajpath.2023.03.015
Abstract

Dry eye syndrome is a common complication in diabetic patients with a prevalence of up to 54.3%. However, the pathogenic mechanisms underlying hyperglycemia-induced tear reduction and dry eye remain less understood. In the present study, we found that both norepinephrine (NE) and tyrosine hydroxylase levels were elevated in the lacrimal gland of diabetic mice, accompanied by increased c-Fos+ cells in the superior cervical ganglion. However, the elimination of NE accumulation by surgical and chemical sympathectomy significantly ameliorated the reduction in tear production, suppressed abnormal inflammation of the lacrimal gland, and improved the severity of dry eye symptoms in diabetic mice. Among various adrenoceptors (AR), the α1 subtype played the predominant role in the regulation of tear production, as treatments of α1AR antagonists improved tear secretion in diabetic mice compared with βAR antagonist propranolol. Moreover, the α1AR antagonist alfuzosin treatment also alleviated functional impairments of the meibomian gland and goblet cells in diabetic mice. Mechanically, the α1AR antagonist rescued the mitochondrial bioenergetic deficit, increased the mitochondrial DNA copy numbers, and elevated the glutathione levels of the diabetic lacrimal gland. Overall, these results deciphered a previously unrecognized involvement of the NE-α1AR-mitochondrial bioenergetics axis in the regulation of tear production in the lacrimal gland, which may provide a potential strategy to counteract diabetic dry eye by interfering with the α1AR activity.

Keywords

Adrenoceptor; Diabetic dry eye; Lacrimal gland; Mitochondria; Norepinephrine; Sympathetic nerve.

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