Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Endocrinology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, China.
J Cell Biochem. 2019 Mar;120(3):4582-4598. doi: 10.1002/jcb.27747. Epub 2018 Oct 15.
Advanced glycation end products (AGEs) play a causative role in the complications involved with diabetes mellitus (DM). Nowadays, DM with hypothyroidism (DM-hypothyroidism) is indicative of an ascended tendency in the combined morbidity. In this study, we examine the role of the receptor (RAGE) played for AGEs in thyroid hormone (TH) secretion via the silent information regulator 1 (SIRT1)/nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) pathway. Blood samples were collected from patients with type 2 DM (T2DM)-hypothyroidism and from patients with T2DM, followed by detection of serum AGEs level. The underlying regulatory mechanisms of RAGE were analyzed in association with the treatment of high glucose, siRNA against RAGE, AGE, SIRT1, or Nrf2 vector in normal immortalized thyroid Nthy-ori 3-1 cells. Serum of patients with T2DM-hypothyroidism indicated promoted levels of AGEs vs those with just T2DM. Both AGEs and high glucose triggered cellular damage, increased oxidative stress, as well as displayed a decreased survival rate along with TH secretion in the Nthy-ori 3-1 cells. Moreover, AGEs and high glucose also led to RAGE upregulation, both SIRT1 and NRF2 downregulation, and the decreased expression of TH secretion-related proteins in Nthy-ori 3-1 cells. Notably, these alternations induced by the AGEs can be reserved by silencing RAGE or upregulating either SIRT1 or Nrf2, indicating a mechanism of regulating TH secretion through the SIRT1/Nrf2 pathway. Collectively, our data proposed that AGEs and high glucose exerted a potent effect on cellular damage and TH deficiency in Nthy-ori 3-1 cells through the RAGE upregulation as well as SIRT1/Nrf2 pathway inactivation. This mechanism may underlie the occurrence of DM-hypothyroidism.
晚期糖基化终产物（AGEs）在糖尿病（DM）相关并发症中起因果作用。如今，伴有甲状腺功能减退（DM-甲状腺功能减退）的 DM 表明合并发病率呈上升趋势。在这项研究中，我们通过沉默信息调节因子 1（SIRT1）/核因子红细胞衍生 2 相关因子 2（Nrf2）通路研究了 AGEs 对甲状腺激素（TH）分泌的受体（RAGE）的作用。收集了 2 型糖尿病（T2DM）-甲状腺功能减退症患者和 T2DM 患者的血液样本，然后检测血清 AGEs 水平。分析了 RAGE 的潜在调节机制，同时还分析了高葡萄糖、RAGE 短发夹 RNA（siRNA）、AGE、SIRT1 或 Nrf2 载体在正常永生化甲状腺 Nthy-ori 3-1 细胞中的治疗作用。与仅患有 T2DM 的患者相比，患有 T2DM-甲状腺功能减退症的患者的血清 AGEs 水平升高。AGEs 和高葡萄糖均引发了细胞损伤、增加了氧化应激，同时还降低了 Nthy-ori 3-1 细胞中的 TH 分泌率。此外，AGEs 和高葡萄糖还导致 RAGE 上调，SIRT1 和 NRF2 下调，以及 Nthy-ori 3-1 细胞中与 TH 分泌相关的蛋白表达减少。值得注意的是，沉默 RAGE 或上调 SIRT1 或 Nrf2 可以保留 AGEs 引起的这些变化，这表明通过 SIRT1/Nrf2 通路调节 TH 分泌的机制。总之，我们的数据表明，AGEs 和高葡萄糖通过 RAGE 上调以及 SIRT1/Nrf2 通路失活对 Nthy-ori 3-1 细胞中的细胞损伤和 TH 缺乏产生了强大的影响。这种机制可能是 DM-甲状腺功能减退症发生的基础。
