Institute of Nephrology, Zhong Da Hospital, Medical School of Southeast University, NO. 87, Ding Jia Qiao Road, Nang Jing, 210009, Jiang Su, China.
Int Urol Nephrol. 2019 Mar;51(3):551-558. doi: 10.1007/s11255-018-2059-7. Epub 2019 Jan 2.
This study aimed to investigate the effects of aspirin on podocyte injury and its underlying mechanisms in diabetic nephropathy (DN).
Eight-week-old male Sprague-Dawley rats were divided into three groups: non-diabetic rats (Control), streptozotocin-induced diabetic rats (DM), and diabetic rats treated with aspirin (DM + Aspirin) for 12 weeks. Intracellular lipid accumulation was evaluated by Oil Red O staining and quantitative free cholesterol assays. Podocyte injury and the levels of COX-2, inflammatory cytokines, and low-density lipoprotein receptor (LDLr) pathway-related proteins were evaluated by electron microscopy, immunohistochemical staining, and Western blotting, respectively.
Lipid levels and urinary albumin-creatinine ratios were higher in the DM rats than in the Control rats. Periodic acid-Schiff staining showed glomerular hypertrophy and mild mesangial area widening in the DM rats. Electron microscopy showed that the podocyte foot processes were significantly flattened or absent in the DM rats. The protein expression levels of WT-1 and nephrin in the podocytes of DM rats were reduced. Interestingly, lipid accumulation in the kidneys of DM rats was significantly increased due to increased protein expression levels of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), SREBP-2, cyclooxygenase-2 (COX-2), and inflammatory cytokines. Confocal immunofluorescent staining showed that COX-2 and WT-1 were co-expressed. Furthermore, COX-2 protein expression levels were positively correlated with LDLr protein expression levels. However, when COX-2 expression was inhibited by aspirin, these changes in the DM rats were significantly attenuated.
Aspirin attenuates podocyte injury in DN, which may be through COX-2-mediated dysregulation of LDLr pathway.
本研究旨在探讨阿司匹林对糖尿病肾病（DN）中足细胞损伤的影响及其作用机制。
将 8 周龄雄性 Sprague-Dawley 大鼠分为三组：非糖尿病大鼠（对照组）、链脲佐菌素诱导的糖尿病大鼠（DM 组）和糖尿病大鼠用阿司匹林治疗（DM+Aspirin 组）12 周。油红 O 染色和定量游离胆固醇测定评估细胞内脂质积累。电镜、免疫组化染色和 Western blot 分别评估足细胞损伤以及 COX-2、炎性细胞因子和低密度脂蛋白受体（LDLr）途径相关蛋白的水平。
DM 组大鼠的血脂水平和尿白蛋白/肌酐比值高于对照组。过碘酸希夫染色显示 DM 组大鼠肾小球肥大，系膜区轻度增宽。电镜显示 DM 组大鼠足细胞的足突明显变平或缺失。DM 组大鼠足细胞 WT-1 和nephrin 的蛋白表达水平降低。有趣的是，由于 LDLr、固醇调节元件结合蛋白裂解激活蛋白（SCAP）、SREBP-2、环氧化酶-2（COX-2）和炎性细胞因子的蛋白表达水平增加，DM 大鼠肾脏中的脂质积累明显增加。共聚焦免疫荧光染色显示 COX-2 和 WT-1 共表达。此外，COX-2 蛋白表达水平与 LDLr 蛋白表达水平呈正相关。然而，当 COX-2 表达被阿司匹林抑制时，DM 大鼠的这些变化明显减弱。
阿司匹林可减轻 DN 中的足细胞损伤，其机制可能与 COX-2 介导的 LDLr 途径失调有关。
