Zhang Yuhan, Wei Mingyan, Wang Xin, Xu Yuan, Zong Rongrong, Lin Xiang, Li Shiying, Chen Wensheng, Liu Zuguo, Chen Qian
Xiamen University Affiliated Xiamen Eye Center, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China.
Front Pharmacol. 2024 Nov 19;15:1490443. doi: 10.3389/fphar.2024.1490443. eCollection 2024.
Diabetic retinopathy (DR) is a common complication of diabetes. Retinal neuronal degeneration is an early event in DR, indicated by the declined electroretinogram (ERG). Dipeptide alanine-glutamine (Ala-Gln) is widely used as a nutritional supplement in the clinic and has anti-inflammatory effects on the gastrointestinal system. Studies also reported that glutamine has beneficial effects on diabetes. This study aimed to investigate the possible therapeutic effects of Ala-Gln in diabetic retinal neurodegeneration and to delineate its mechanism of action.
The Streptozotocin (STZ)-induced rat model was used as a DR model. ERG was used to measure the neuronal function of the retina. Western blot analysis was performed to test the expression of proteins. Immunofluorescence staining was used for the detection and localization of proteins.
In diabetic rats, the amplitudes of ERG were declined, while Ala-Gln restored the declined ERG. Retinal levels of inflammatory factors were significantly decreased in Ala-Gln-treated diabetic rats. Ala-Gln mitigated the declined levels of glutamine synthetase and ameliorated the upregulated levels of glial fibrillary acidic protein (GFAP) in diabetic retinas. Moreover, Ala-Gln upregulated the glycolytic enzymes pyruvate kinase isozymes 2 (PKM2), lactate dehydrogenase A (LDHA) and LDHB and stimulated the mTOR signaling pathway in diabetic retinas. The mitochondrial function was improved after the treatment of Ala-Gln in diabetic retinas.
Ala-Gln ameliorates retinal neurodegeneration by reducing inflammation and enhancing glucose metabolism and mitochondrial function in DR. Therefore, manipulation of metabolism by Ala-Gln may be a novel therapeutic avenue for retinal neurodegeneration in DR.
糖尿病视网膜病变（DR）是糖尿病常见的并发症。视网膜神经元变性是DR的早期事件，表现为视网膜电图（ERG）下降。二肽丙氨酸 - 谷氨酰胺（Ala - Gln）在临床上广泛用作营养补充剂，对胃肠道系统具有抗炎作用。研究还报道谷氨酰胺对糖尿病有益。本研究旨在探讨Ala - Gln对糖尿病性视网膜神经变性的可能治疗作用，并阐明其作用机制。
采用链脲佐菌素（STZ）诱导的大鼠模型作为DR模型。用ERG测量视网膜的神经元功能。进行蛋白质印迹分析以检测蛋白质表达。免疫荧光染色用于蛋白质的检测和定位。
在糖尿病大鼠中，ERG的振幅下降，而Ala - Gln使下降的ERG恢复。在Ala - Gln处理的糖尿病大鼠中，视网膜炎症因子水平显著降低。Ala - Gln减轻了糖尿病视网膜中谷氨酰胺合成酶水平的下降，并改善了胶质纤维酸性蛋白（GFAP）上调的水平。此外，Ala - Gln上调了糖酵解酶丙酮酸激酶同工酶2（PKM2）、乳酸脱氢酶A（LDHA）和LDHB，并刺激了糖尿病视网膜中的mTOR信号通路。在糖尿病视网膜中用Ala - Gln治疗后，线粒体功能得到改善。
Ala - Gln通过减轻DR中的炎症、增强葡萄糖代谢和线粒体功能来改善视网膜神经变性。因此，通过Ala - Gln调节代谢可能是DR中视网膜神经变性的一种新的治疗途径。
