SGLT2 inhibitor-empagliflozin treatment ameliorates diabetic retinopathy manifestations and exerts protective effects associated with augmenting branched chain amino acids catabolism and transportation in db/db mice
SGLT2 inhibitor-empagliflozin treatment ameliorates diabetic retinopathy manifestations and exerts protective effects associated with augmenting branched chain amino acids catabolism and transportation in db/db mice
复制标题
SGLT2 抑制剂恩格列净治疗可改善 db/db 小鼠糖尿病视网膜病变的表现，并发挥与增强支链氨基酸分解代谢和运输相关的保护作用
DOI：
10.1016/j.biopha.2022.113222
复制
发表时间：
2022-06-04
影响因子：
7.5
通讯作者：
Wang, Haiyan
中科院分区：
文献类型：
--
作者：
Gong, Qiaoyun;Zhang, Rulin;Wang, Haiyan
恩帕列净（EMPA）是第一个能显著降低2型糖尿病心血管和肾脏并发症的钠-葡萄糖共转运蛋白2抑制剂。鉴于此，我们推测EMPA可能具有干预糖尿病视网膜病变（DR）的潜力，这是另一种糖尿病特异性微血管并发症。采用不同时间的EMPA处理Db/ Db小鼠，观察视网膜的变化及相关机制。EMPA在db/db小鼠中有效平衡体重和血糖水平，减轻眼水肿和微动脉瘤。EMPA显著抑制糖尿病视网膜氧化应激、细胞凋亡，恢复视网膜紧密连接。MS/MS分析显示，EMPA抑制了db/db视网膜中异常支链氨基酸（BCAAs）的积累，从而抑制了雷帕霉素激活的哺乳动物靶点，下调了炎症和血管生成因子，包括糖尿病诱导的tnf - α、IL-6、VCAM-1和VEGF。此外，支链α -酮酸（BCKAs）是BCAAs的分解产物，在糖尿病视网膜中增加，并随着EMPA的应用而减少。此外，支链酮酸脱氢酶激酶（BCKDK）升高，BCKDHA和BCKDHB降低。这可以通过EMPA治疗逆转，从而促进BCAAs的分解代谢，减少BCAAs和BCKAs在糖尿病视网膜中的积累。血浆中BCAAs的高水平和l型氨基酸转运蛋白1 （LAT1）的增强是糖尿病视网膜BCAAs高水平的原因，EMPA可以抑制BCAAs的高水平。总的来说，EMPA可以改善DR的表现。支链氨基酸分解代谢和摄入的正常化可能在这一过程中起作用。本研究支持EMPA作为预防DR的药物。
Empagliflozin (EMPA) is the first sodium-glucose co-transporter 2 inhibitor to significantly reduce cardiovascular and kidney complications in type 2 diabetes mellitus. Given this, we speculate that EMPA may have the potential to intervene in diabetic retinopathy (DR), which is another diabetes-specific microvascular complication. Db/db mice were treated with EMPA for different periods to observe the retinas and related mechanisms. EMPA effectively balanced body weight and blood glucose levels, mitigated ocular edema and microaneurysm in db/db mice. EMPA significantly inhibited oxidative stress, apoptosis and recovered tight junction in diabetic retinas. MS/MS analyses showed that EMPA suppressed aberrant branched-chain amino acid (BCAAs) accumulation in db/db retinas, which led to the inhibition of the mammalian target of rapamycin activation, downregulation of inflammation, and angiogenic factors, including TNF-alpha, IL-6, VCAM-1, and VEGF induced by diabetes. Furthermore, branched-chain alpha-keto acids (BCKAs), which are catabolites of BCAAs, were increased in diabetic retinas and decreased with EMPA application. Moreover, branched-chain ketoacid dehydrogenase kinase (BCKDK) was enhanced, BCKDHA and BCKDHB were decreased in diabetic retinas. This could be reversed by EMPA treatment, thus promoting BCAAs catabolism to decrease BCAAs and BCKAs accumulation in diabetic retinas. The high levels of BCAAs in the plasma and enhanced L-type amino acid transporter 1 (LAT1) were responsible for the high levels of BCAAs in diabetic retinas, which could be inhibited by EMPA. Overall, EMPA could ameliorate DR manifestations. The normalization of BCAAs catabolism and intake may play a role in this process. This study supports EMPA as a protective drug against DR.