Liu Hong, Wang Quan, Shi Ge, Yang Wenqiang, Zhang Yanmin, Chen Weidong, Wan Sheng, Xiong Fei, Wang Zengsi
Department of Nephrology, Wuhan No. 1 Hospital, Wuhan, Hubei, 430022, People's Republic of China.
Department of Central Laboratory, Wuhan No. 1 Hospital, Wuhan, Hubei, 430022, People's Republic of China.
Diabetes Metab Syndr Obes. 2021 Mar 18;14:1253-1266. doi: 10.2147/DMSO.S299375. eCollection 2021.
The activation of autophagy has potential protective effect on diabetic nephropathy (DN) podocyte injury, and the AMPK/mTOR signaling pathway is an important regulatory pathway of autophagy. Emodin has been reported to effectively delay DN progression; however, the therapeutic mechanisms involved in vivo remain ambiguous. The present study aimed to elucidate the mechanism of emodin in improving renal tissue and podocyte injury in DN by regulating the AMPK/mTOR-autophagy signaling pathway.
All rats were divided into 4 groups: a Sham group, a Vehicle group, a low-dose emodin (LD-Emo) group (20 mg/kg/day) and a high-dose emodin (HD-Emo) group (40 mg/kg/day). The different doses of Emo and distilled water were daily administrated for 8 weeks after the induction of DN by the unilateral nephrectomy combined with intraperitoneal injections of streptozotocin (STZ). The rats' general status, blood glucose, biochemical parameters, urinary protein excretion, renal histological changes and cell apoptosis in renal tissue, as well as the key protein expressions in the AMPK/mTOR signaling pathway and apoptosis-related proteins were examined, respectively.
Emodin ameliorated the general condition, kidney weight and urinary protein excretion of the rats, but has little influence on serum biochemical parameters and did not lower blood glucose; emodin attenuated renal fibrosis including the cell numbers, extracellular matrix rate and collagen area in glomerulus, simultaneously relieved podocyte foot process fusion, up-regulated the expression of nephrin protein and suppressed glomerular and tubular epithelial cell apoptosis. In addition, emodin can induce and enhance autophagy in podocytes including increased expression of LC3-II/I, Beclin-1, p-AMPK protein and decreased expression of p62, p-mTOR protein, as well as increased autophagosomes in podocytes.
We have demonstrated that emodin, as a natural regulator in vivo, reduced proteinuria and alleviated renal fibrosis without affecting hyperglycemia in DN rats. The potential mechanisms by which emodin exerts its renoprotective effects in vivo are through suppressing cell apoptosis and enhancing autophagy of podocytes via the AMPK/mTOR signaling pathway in the kidney.
自噬的激活对糖尿病肾病（DN）足细胞损伤具有潜在保护作用，且AMPK/mTOR信号通路是自噬的重要调控途径。据报道，大黄素可有效延缓DN进展；然而，其体内治疗机制仍不明确。本研究旨在通过调节AMPK/mTOR-自噬信号通路阐明大黄素改善DN大鼠肾组织和足细胞损伤的机制。
将所有大鼠分为4组：假手术组、溶剂对照组、低剂量大黄素（LD-Emo）组（20mg/kg/天）和高剂量大黄素（HD-Emo）组（40mg/kg/天）。通过单侧肾切除联合腹腔注射链脲佐菌素（STZ）诱导DN后，每日给予不同剂量的大黄素和蒸馏水，持续8周。分别检测大鼠的一般状况、血糖、生化指标、尿蛋白排泄、肾组织学变化及细胞凋亡情况，以及AMPK/mTOR信号通路关键蛋白表达和凋亡相关蛋白表达。
大黄素改善了大鼠的一般状况、肾脏重量和尿蛋白排泄，但对血清生化指标影响较小且未降低血糖；大黄素减轻了肾纤维化，包括肾小球细胞数量、细胞外基质比例和胶原面积，同时缓解了足细胞足突融合，上调了nephrin蛋白表达并抑制了肾小球和肾小管上皮细胞凋亡。此外，大黄素可诱导并增强足细胞自噬，包括LC3-II/I、Beclin-1、p-AMPK蛋白表达增加，p62、p-mTOR蛋白表达降低，以及足细胞中自噬体增多。
我们已证明，大黄素作为体内天然调节剂，可降低DN大鼠蛋白尿并减轻肾纤维化，而不影响高血糖。大黄素在体内发挥肾保护作用的潜在机制是通过肾脏中的AMPK/mTOR信号通路抑制细胞凋亡并增强足细胞自噬。
