Yuting Li

Purpose: High altitude retinopathy (HAR) is a retinal functional disorder caused by inadequate adaptation after exposure to high altitude. However, the cellular and molecular mechanisms underlying retinal dysfunction remain elusive. Retinal ganglion cell (RGC) injury is the most important pathological basis for most retinal and optic nerve diseases. Studies focusing on RGC injury after high-altitude exposure (HAE) are scanty. Therefore, the present study sought to explore both functional and morphological alterations of RGCs after HAE. Methods: A mouse model of acute hypobaric hypoxia was established by mimicking the conditions of a high altitude of 5000 m. After HAE for 2, 4, 6, 10, 24, and 72 hours, the functional and morphological alterations of RGCs were assessed using retinal hematoxylin and eosin (H&E) sections, retinal whole mounts, transmission electron microscopy (TEM), and the photopic negative response (PhNR) of the electroretinogram. Results: Compared with the control group, the thickness of the ganglion cell layer and retinal nerve fiber layer increased significantly, RGC loss remained significant, and the amplitudes of a-wave, b-wave, and PhNR were significantly reduced after HAE. In addition, RGCs and their axons exhibited an abnormal ultrastructure after HAE, including nuclear membrane abnormalities, uneven distribution of chromatin in the nucleus, decreased cytoplasmic electron density, widening and vacuolization of the gap between axons, loosening and disorder of myelin sheath structure, widening of the gap between myelin sheath and axon membrane, decreased axoplasmic density, unclear microtubule and nerve fiber structure, and abnormal mitochondrial structure (mostly swollen, with widened membrane gaps and reduced cristae and vacuolization). Conclusions: The study findings confirm that the morphology and function of RGCs are damaged after HAE. These findings lay the foundation for further study of the specific molecular mechanisms of HAR and promote the effective prevention.

Hypobaric hypoxia is the main cause of high-altitude retinopathy (HAR). Retinal oedema is the key pathological change in HAR. However, its pathological mechanism is not clear. In this study, a 5000-m hypobaric hypoxic environment was simulated. Haematoxylin and eosin (H&E) staining and electrophysiological (ERG) detection were used to observe the morphological and functional changes in the retina of mice under hypobaric hypoxia for 2–72 h. Toluidine blue staining and transmission electron microscopy were used to observe the morphology of Müller cells in the hypobaric hypoxia groups. The functional changes and oedema mechanism of Müller cells were detected by immunofluorescence and western blotting. The expression levels of glutamine synthetase (GS), glial fibrillary acidic protein (GFAP), aquaporin 4 (AQP4), and inwardly rectifying potassium channel subtype 4.1 (Kir4.1) in Müller cells were quantitatively analysed. This study revealed that retinal oedema gradually increased with prolonged exposure to a 5000-m hypobaric hypoxic environment. In addition, the ERG showed that the time delay and amplitude of the a-wave and b-wave decreased. The expression of GS decreased, and the expression of GFAP increased in Müller cells after exposure to hypobaric hypoxia for 4 h. At the same time, retinal AQP4 expression increased, and Kir4.1 expression decreased. The oedema and functional changes in Müller cells are consistent with the time point of retinal oedema. In conclusion, Müller cell oedema is involved in retinal oedema induced by hypobaric hypoxia. An increase in AQP4 and a decrease in Kir4.1 are the main causes of Müller cell oedema caused by hypobaric hypoxia.

Fibrosis initially appears as a normal response to damage, where activated fibroblasts produce large amounts of the extracellular matrix (ECM) during the wound healing process to assist in the repair of injured tissue. However, the excessive accumulation of the ECM, unresolved by remodeling mechanisms, leads to organ dysfunction. Connexins, a family of transmembrane channel proteins, are widely recognized for their major roles in fibrosis, the epithelial–mesenchymal transition (EMT), and wound healing. Efforts have been made in recent years to identify novel mediators and targets for this regulation. Connexins form gap junctions and hemichannels, mediating communications between neighboring cells and inside and outside of cells, respectively. Recent evidence suggests that connexins, beyond forming channels, possess channel-independent functions in fibrosis, the EMT, and wound healing. One crucial channel-independent function is their role as the primary functional component for cell adhesion. Other channel-independent functions of connexins involve their roles in mitochondria and exosomes. This review summarizes the latest advances in the channel-dependent and independent roles of connexins in fibrosis, the EMT, and wound healing, with a particular focus on eye diseases, emphasizing their potential as novel, promising therapeutic targets.