Hyperglycemia Induces Tear Reduction and Dry Eye in Diabetic Mice through the Norepinephrine-a1 Adrenergic Receptor-Mitochondrial Impairment Axis of Lacrimal Gland

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. The present study indicated that both norepinephrine (NE) and tyrosine hydroxylase levels were elevated in the lacrimal gland of diabetic mice, accompanied by increased Fos proto-oncogene (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 adrenergic receptors (ARs), the a1 subtype played a predominant role in the regulation of tear production, as treatments of a1AR antagonists improved tear secretion in diabetic mice compared with DAR antagonist propranolol. Moreover, the a1AR antagonist alfuzosin treatment also alleviated functional impairments of the meibomian gland and goblet cells in diabetic mice. Mechanically, the a1AR 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-a1AR-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 a1AR activity.

Automated summary

Dry eye syndrome is a common complication in diabetic patients, but the mechanisms behind hyperglycemia-induced tear reduction and dry eye are not well understood. This study found that elevated levels of norepinephrine and tyrosine hydroxylase in the lacrimal gland of diabetic mice were associated with increased c-FOS+ cells in the superior cervical ganglion. However, the elimination of norepinephrine accumulation significantly improved tear production and reduced inflammation in the lacrimal gland, suggesting a potential strategy for treating diabetic dry eye by targeting the a1 adrenergic receptor.