Single-Cell RNA Sequencing of Retina Reveals Nna1 Upregulation in Myopic Diabetic Retinopathy as a Protective Factor Against Diabetic Damage.

Abstract

Epidemiological and clinical observations suggest a substantial reduction in the risk and severity of diabetic retinopathy (DR) among individuals with myopia. However, the impact of myopia on DR and its underlying mechanisms remains unclear. Herein, by establishing a form-deprivation myopia (FDM) and lens-induced myopia (LIM) models in diabetic db/db mice, a significant reduction of retinal vascular lesions is identified in db/db mice after myopia modeling. Single-cell transcriptomic analysis further reveals elevated expression of Nervous system nuclear protein induced by axotomy 1 (Nna1) in Müller cells of db/db mice subjected to FDM compared to db/db alone, alongside decreased Nna1 expression in db/db compared to db/m mice. Knockdown of Nna1 in FDM-treated db/db eyes reverses the protective effects of myopia on DR. Transcriptomic profiling links reduced Nna1 expression to enhanced apoptotic and autophagic signaling pathways in Müller cells. Further in vivo and in vitro experiments confirm that Nna1 overexpression suppresses microtubule hyper-glutamylation, thereby reducing autophagy and apoptosis levels in Müller cells, and ameliorating DR progression. These findings suggest that Nna1 may play a key role in protecting Müller cells and maintaining the integrity of the neurovascular unit, thereby contributing to the protective effects of myopia in DR and representing a potential molecular target for early intervention and treatment of DR.