Department of Basic Medical Science, Jiangsu Vocational College of Medicine, Yancheng, Jiangsu Province, China; College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China; Chemistry and Life Science College, Nanjing University Jinling College, Nanjing, Jiangsu Province, China.
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China; Hanlin College, Nanjing University of Chinese Medicine, Taizhou, Jiangsu Province, China.
Life Sci. 2020 Jul 1;252:117653. doi: 10.1016/j.lfs.2020.117653. Epub 2020 Apr 8.
BACKGROUND/AIMS: Rehmanniae Radix (RR) and Cornus officinalis (CO) are a typical herbal pair used to treat diabetic nephropathy (DN) in clinical practice. DN can be effectively treated by catalpol (Cat) and loganin (Log), the main active components of RR and CO respectively, through combating apoptosis, oxidative stress and inflammation. Herein, a spontaneous DN and podocyte injury model induced by advanced glycation end products (AGEs), i.e. KK-Ay mice, was used to explore the cooperative effects of Log and Cat on DN and the mechanism targeting the AGEs-RAGE (receptor for AGE) pathway.
Log and Cat alone or in combination mitigated diabetic symptoms, decreased the level of fasting blood glucose, and increased that of serum insulin. The two drugs alone or in combination protected renal function from damage, prevented extracellular matrix hyperplasia and glycogen deposition, as well as alleviated the loss of podocytes detected by histological assay and immunohistochemistry. Flow cytometry revealed that Log and Cat alone or in combination relieved the apoptosis of AGEs-induced podocytes in vitro. Silencing RAGE by RNA interference played a protective role in podocyte apoptosis, whereas overexpression of it worked oppositely. Western blot exhibited that Log and Cat alone or in combination inhibited the activation of RAGE/p38 MAPK/p65 NF-κB and RAGE/Nox4/p65 NF-κB pathways in podocytes. The inhibitory effects of drug combination were more evident than those of individual treatments.
Log and Cat cooperatively resisted the apoptosis of podocytes upon DN by targeting AGEs-RAGE and its downstream pathways p38 MAPK and Nox4.
背景/目的：地黄（RR）和山茱萸（CO）是临床上用于治疗糖尿病肾病（DN）的典型药对。分别作为 RR 和 CO 的主要活性成分，梓醇（Cat）和马钱苷（Log）通过对抗细胞凋亡、氧化应激和炎症，可以有效治疗 DN。本研究采用晚期糖基化终产物（AGEs）诱导的自发性 DN 和足细胞损伤模型（即 KK-Ay 小鼠），探讨 Log 和 Cat 对 DN 的协同作用及针对 AGEs-RAGE（AGE 受体）通路的作用机制。
Log 和 Cat 单独或联合应用均可改善糖尿病症状，降低空腹血糖水平，提高血清胰岛素水平。两药单独或联合应用均可保护肾功能免受损伤，防止细胞外基质增生和糖原沉积，并通过组织学和免疫组化检测减轻足细胞丢失。流式细胞术显示 Log 和 Cat 单独或联合应用可减轻 AGEs 诱导的体外足细胞凋亡。RNA 干扰沉默 RAGE 对足细胞凋亡起保护作用，而过表达 RAGE 则起相反作用。Western blot 显示 Log 和 Cat 单独或联合应用可抑制 RAGE/p38 MAPK/p65 NF-κB 和 RAGE/Nox4/p65 NF-κB 通路在足细胞中的激活。药物联合的抑制作用比单独用药更明显。
Log 和 Cat 通过靶向 AGEs-RAGE 及其下游通路 p38 MAPK 和 Nox4，协同抵抗 DN 时足细胞的凋亡。
