Department of Cardiology, Liyuan Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China.
College of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan 430065, China.
Endocr Metab Immune Disord Drug Targets. 2022;22(8):862-873. doi: 10.2174/1871530322666220110161458.
Cortex Mori Radicis (CMR) has been reported to possess antipyretic, anticonvulsant, anti-allergic, anti-inflammatory, and anti-diabetic effects. In this study, we aimed to investigate the effect of CMR on streptozotocin (STZ)-induced diabetic renal injury in mice and explore the underlying mechanism.
Mice were gavaged with different doses of CMR for continuous 7 days. Then, STZ (50 mg/kg) was applied to induce renal injury associated with type 1 diabetes. Firstly, blood glucose levels and metabolic parameters were evaluated, including weight, food intake, and excrement. HE and PAS staining were performed to examine renal histological changes. Renal inflammation, fibrosis, and oxidative stress were assayed by real-time PCR and ELISA, separately. Additionally, podocyte- related markers, such as nephrin and wilms' tumor-1 (WT-1), were detected by immunohistochemical staining and Western blot separately. Lastly, expression of transient receptor potential canonical channel 6 (TRPC6) and activation of MAPK signaling pathways were assayed.
CMR pretreatment significantly lowered the blood glucose levels, suppressed renal inflammation, fibrosis, and oxidative stress, and relieved renal pathological injury, accompanying the inhibition of nephrin and WT-1 expression in STZ-induced diabetic mice. Moreover, CMR decreased the expression of TRPC6 and suppressed the phosphorylation of ERK, but not P38 MAPK and JNK. Notably, the application of hyperforin, a specific activator of TRPC6, significantly abrogated the hypoglycemic effect of CMR and reversed the suppression of CMR on TRPC6 expression and ERK activation in the diabetic mice.
Our findings indicated that CMR attenuated early renal injury in STZ-induced diabetic mice by inhibiting ERK signaling via regulation of TRPC6, suggesting that CMR can be considered as a promising candidate for the management of diabetes-related renal complications.
桑白皮（CMR）具有解热、抗惊厥、抗过敏、抗炎和抗糖尿病作用。本研究旨在探讨 CMR 对链脲佐菌素（STZ）诱导的糖尿病肾病小鼠的作用及其机制。
连续 7 天给小鼠灌胃不同剂量的 CMR。然后，用 STZ（50mg/kg）诱导与 1 型糖尿病相关的肾损伤。首先，评估血糖水平和代谢参数，包括体重、食物摄入和粪便。通过 HE 和 PAS 染色检查肾组织学变化。通过实时 PCR 和 ELISA 分别测定肾炎症、纤维化和氧化应激。此外，通过免疫组化染色和 Western blot 分别检测足细胞相关标志物，如nephrin 和 wilms' 肿瘤-1（WT-1）。最后，检测瞬时受体电位经典通道 6（TRPC6）的表达和 MAPK 信号通路的激活。
CMR 预处理显著降低血糖水平，抑制肾炎症、纤维化和氧化应激，减轻 STZ 诱导的糖尿病小鼠的肾病理损伤，同时抑制 nephrin 和 WT-1 的表达。此外，CMR 降低 TRPC6 的表达并抑制 ERK 的磷酸化，但不抑制 P38 MAPK 和 JNK。值得注意的是，特异性激活 TRPC6 的贯叶金丝桃素的应用显著消除了 CMR 的降血糖作用，并逆转了 CMR 对糖尿病小鼠 TRPC6 表达和 ERK 激活的抑制作用。
我们的研究结果表明，CMR 通过调节 TRPC6 抑制 ERK 信号通路减轻 STZ 诱导的糖尿病小鼠早期肾损伤，表明 CMR 可作为治疗糖尿病相关肾脏并发症的有前途的候选药物。
