Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Oxid Med Cell Longev. 2020 Aug 6;2020:6104375. doi: 10.1155/2020/6104375. eCollection 2020.
Endoplasmic reticulum (ER) stress has been reported to play a pivotal role in diabetic nephropathy (DN). AdipoRon is a newly developed adiponectin receptor agonist that provides beneficial effects for diabetic mice; however, its underlying mechanism remains to be delineated. Here, we demonstrated increased expression levels of ER stress markers, accompanied by upregulated levels of proinflammatory cytokines and increased expression of collagen I, fibronectin, Bax, and cleaved caspase 3 in the kidneys of db/db mice compared with control mice. Decreased expression of adiponectin receptor 1 (AdipoR1) and phosphorylated 5'AMP-activated kinase (p-AMPK) was also observed in the kidneys of db/db mice. However, these alterations were partially reversed by intragastric gavage with AdipoRon. , AdipoRon alleviated high-glucose-induced ER stress, oxidative stress, and apoptosis in HK-2 cells, a human tubular cell line. Moreover, AdipoRon restored the expression of AdipoR1 and p-AMPK in HK-2 cells exposed to high-glucose conditions. Additionally, these effects were partially abrogated by pretreatment with AdipoR1 siRNA, but this abrogation was ameliorated by cotreatment with AICAR, an AMPK activator. Furthermore, the effects of AdipoRon were also partially abolished by cotreatment with compound C. Together, these results suggest that AdipoRon exerts favorable effects on diabetes-induced tubular injury in DN by inhibiting ER stress mediated by the AdipoR1/p-AMPK pathway.
内质网（ER）应激已被报道在糖尿病肾病（DN）中发挥关键作用。AdipoRon 是一种新开发的脂联素受体激动剂，它对糖尿病小鼠有有益的影响；然而，其潜在的机制仍有待阐明。在这里，我们发现在 db/db 小鼠的肾脏中，与对照小鼠相比，内质网应激标志物的表达水平增加，伴随促炎细胞因子水平上调，以及胶原 I、纤连蛋白、Bax 和 cleaved caspase 3 的表达增加。db/db 小鼠肾脏中脂联素受体 1（AdipoR1）和磷酸化 5'AMP 激活的蛋白激酶（p-AMPK）的表达也降低。然而，这些改变部分被 AdipoRon 灌胃逆转。AdipoRon 减轻了 HK-2 细胞（一种人肾小管细胞系）中高葡萄糖诱导的 ER 应激、氧化应激和细胞凋亡。此外，AdipoRon 恢复了高葡萄糖条件下 HK-2 细胞中 AdipoR1 和 p-AMPK 的表达。此外，用 AdipoR1 siRNA 预处理部分阻断了这些作用，但用 AMPK 激活剂 AICAR 共同处理可改善这种阻断。此外，用 Compound C 共同处理也部分阻断了 AdipoRon 的作用。总之，这些结果表明，AdipoRon 通过抑制 AdipoR1/p-AMPK 通路介导的 ER 应激，对糖尿病诱导的 DN 肾小管损伤发挥有利作用。
