Shi Chen, Zhang Qilin, Li Yufeng, Zhao Junjun, Wang Cong, Zhang Yu
Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.
Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China.
BMC Cardiovasc Disord. 2024 Dec 18;24(1):704. doi: 10.1186/s12872-024-04427-4.
Cardiovascular and renal complications of type 2 diabetes are the main causes of death in diabetic patients. Clinical studies have found that polyethylene glycol loxenatide (PEG-Loxe), a GLP-1 analog widely used to treat type 2 diabetes, boosts renal and cardiac functions in diabetic patients. However, its mechanism of action remains to be elucidated.
Using injury models of HK-2 human renal proximal tubular epithelial cells and H9C2 rat myocardial cells, as well as db/db mouse models of type 2 diabetes, this study assessed the protective effects of PEG-Loxe on T2DM mice kidneys and hearts and revealed their mechanisms of action.
PEG-Loxe treatment significantly reduced the contents of serum creatinine, urea nitrogen, and 24 h urine protein, alleviated glomerular injury and inflammatory reaction, markedly elevated cardiac left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) levels, diminished pathological injuries in cardiac tissues, and improved renal and cardiac functions in db/db mice. In addition, PEG-Loxe considerably decreased the GRP78 mRNA and protein expressions of GRP78, p-eIF2α, ATF4, and CHOP in the kidneys of T2DM mice, inhibited GRP78/PERK/eIF2α pathway-related proteins in HK-2 cells cultured in high glucose concentrations, subdued renal endoplasmic reticulum stress, and eased renal injury in T2DM mice. PEG-Loxe also obstructed the TLR4/NF-κB inflammatory pathway and myocardial apoptosis and mitigated cardiac trauma in T2DM by reducing TLR4, MyD88, and p-NF-κBp65 protein expressions in cardiac tissues. The H9C2 cell experiment further confirmed PEG-Loxe's ability to protect the cardiovascular system of T2DM patients by inhibiting the TLR4/NF-κB inflammatory pathway and lessening LDH and CK-MB levels.
We showed that PEG-Loxe could decrease renal stress response and improve renal injury in T2DM by inhibiting endoplasmic reticulum stress via the GRP78/PERK/eIF2α pathway. Additionally, PEG-Loxe could hinder the TLR4/NF-κB inflammatory pathway and myocardial apoptosis and boost cardiac function, thus exerting protective effects on the cardiovascular system in T2DM.
2型糖尿病的心血管和肾脏并发症是糖尿病患者死亡的主要原因。临床研究发现，聚乙二醇洛塞那肽（PEG-Loxe）作为一种广泛用于治疗2型糖尿病的胰高血糖素样肽-1（GLP-1）类似物，可改善糖尿病患者的肾脏和心脏功能。然而，其作用机制仍有待阐明。
本研究利用人肾近端小管上皮细胞HK-2和大鼠心肌细胞H9C2的损伤模型，以及2型糖尿病db/db小鼠模型，评估了PEG-Loxe对2型糖尿病小鼠肾脏和心脏的保护作用，并揭示其作用机制。
PEG-Loxe治疗显著降低了血清肌酐、尿素氮和24小时尿蛋白含量，减轻了肾小球损伤和炎症反应，显著提高了心脏左心室射血分数（LVEF）和缩短分数（LVFS）水平，减少了心脏组织的病理损伤，改善了db/db小鼠的肾脏和心脏功能。此外，PEG-Loxe显著降低了2型糖尿病小鼠肾脏中葡萄糖调节蛋白78（GRP78）、磷酸化真核翻译起始因子2α（p-eIF2α）、活化转录因子4（ATF4）和C/EBP同源蛋白（CHOP）的mRNA和蛋白表达，抑制了高糖培养的HK-2细胞中GRP78/蛋白激酶R样内质网激酶（PERK）/eIF2α途径相关蛋白，减轻了2型糖尿病小鼠的肾脏内质网应激并缓解了肾脏损伤。PEG-Loxe还通过降低心脏组织中Toll样受体4（TLR4）、髓样分化因子88（MyD88）和磷酸化核因子κB p65（p-NF-κBp65）蛋白表达，阻断TLR4/核因子κB（NF-κB）炎症途径和心肌细胞凋亡，减轻了2型糖尿病的心脏损伤。H9C2细胞实验进一步证实了PEG-Loxe通过抑制TLR4/NF-κB炎症途径和降低乳酸脱氢酶（LDH）及肌酸激酶同工酶（CK-MB）水平来保护2型糖尿病患者心血管系统的能力。
我们发现PEG-Loxe可通过GRP78/PERK/eIF2α途径抑制内质网应激，降低2型糖尿病的肾脏应激反应并改善肾脏损伤。此外，PEG-Loxe可阻断TLR4/NF-κB炎症途径和心肌细胞凋亡，增强心脏功能，从而对2型糖尿病的心血管系统发挥保护作用。
