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

## TL;DR

Myopia reduces diabetic retinopathy risk, possibly through increased Nna1 expression in Müller cells, which protects retinal health.

## Contribution

This study identifies Nna1 as a protective factor in myopic diabetic retinopathy through single-cell RNA sequencing and mechanistic experiments.

## Key findings

- Myopia models in diabetic mice show reduced retinal vascular lesions and upregulated Nna1 in Müller cells.
- Nna1 overexpression suppresses microtubule hyper-glutamylation and reduces apoptosis and autophagy in Müller cells.
- Nna1 knockdown reverses the protective effects of myopia on diabetic retinopathy.

## 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.

This study investigates a schematic overview of the mechanistic pathways. The relationship between myopia and DR has long been of clinical interest. In diabetic mice, Nna1 expression is downregulated, whereas in diabetic mice with FDM, Nna1 expression is upregulated–particularly in Müller cells–accompanied by decreased vascular endothelial growth factor (VEGF) expression, reduced vascular leakage, a lower endothelial‐to‐pericyte ratio, and fewer microaneurysms. Overexpression of Nna1 is found to inhibit diabetic retinal neurovascular unit damage by regulating autophagy and apoptosis in Müller cells through the inhibition of tubulin hyper‐glutamylation.