Matsui Takanori, Higashimoto Yuichiro, Nishino Yuri, Nakamura Nobutaka, Fukami Kei, Yamagishi Sho-Ichi
Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
Department of Chemistry, Kurume University School of Medicine, Kurume, Japan.
Diabetes. 2017 Jun;66(6):1683-1695. doi: 10.2337/db16-1281. Epub 2017 Apr 6.
The interaction of advanced glycation end products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy. We screened DNA aptamers directed against RAGE (RAGE-aptamers) in vitro and examined the effects on the development and progression of diabetic nephropathy in streptozotocin-induced diabetic rats. RAGE-aptamer bound to RAGE with a of 5.68 nmol/L and resultantly blocked the binding of AGEs to RAGE. When diabetic rats received continuous intraperitoneal injection of RAGE-aptamer from week 7 to 11 of diabetes, the increases in renal NADPH oxidase activity, oxidative stress generation, AGE, RAGE, inflammatory and fibrotic gene and protein levels, macrophage and extracellular matrix accumulation, and albuminuria were significantly suppressed, which were associated with improvement of podocyte damage. Two-week infusion of RAGE-aptamer just after the induction of diabetes also inhibited the AGE-RAGE-oxidative stress system and MCP-1 levels in the kidneys of 8-week-old diabetic rats and simultaneously ameliorated podocyte injury and albuminuria. Moreover, RAGE-aptamer significantly suppressed the AGE-induced oxidative stress generation and inflammatory and fibrotic reactions in human cultured mesangial cells. The findings suggest that continuous infusion of RAGE-aptamer could attenuate the development and progression of experimental diabetic nephropathy by blocking the AGE-RAGE axis.
晚期糖基化终末产物（AGEs）与其受体（RAGE）的相互作用在糖尿病肾病中起核心作用。我们在体外筛选了针对RAGE的DNA适配体（RAGE-适配体），并研究了其对链脲佐菌素诱导的糖尿病大鼠糖尿病肾病发生发展的影响。RAGE-适配体与RAGE结合，解离常数为5.68 nmol/L，从而阻断了AGEs与RAGE的结合。当糖尿病大鼠在糖尿病第7周至11周期间连续腹腔注射RAGE-适配体时，肾NADPH氧化酶活性增加、氧化应激产生、AGE、RAGE、炎症和纤维化基因及蛋白水平、巨噬细胞和细胞外基质积聚以及蛋白尿均受到显著抑制，这与足细胞损伤的改善相关。在糖尿病诱导后立即进行为期两周的RAGE-适配体输注，也抑制了8周龄糖尿病大鼠肾脏中的AGE-RAGE-氧化应激系统和MCP-1水平，同时改善了足细胞损伤和蛋白尿。此外，RAGE-适配体显著抑制了人培养系膜细胞中AGE诱导的氧化应激产生以及炎症和纤维化反应。这些发现表明，持续输注RAGE-适配体可通过阻断AGE-RAGE轴减轻实验性糖尿病肾病的发生和发展。
