Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
Mol Immunol. 2018 Dec;104:61-68. doi: 10.1016/j.molimm.2018.10.021. Epub 2018 Nov 12.
Diabetic nephropathy (DN) contributes to end-stage renal disease and kidney dysfunction with a proverbial feature of podocyte injury. Inflammation and insulin resistance is recently implicated in the pathogenesis of diabetic kidney injury. Celastrol exerts critical roles in inflammatory diseases and injury progression. However, its function and mechanism in DN remains elusive. Here, celastrol dose-dependently restored podocyte viability under high glucose (HG) conditions, but with little cytotoxicity in podocyte. Preconditioning with celastrol counteracted HG-evoked cell apoptosis, LDH release, ROS production and podocyte depletion. Additionally, HG-elevated high transcripts and secretions of pro-inflammatory cytokines were reversed following celastrol treatment, including IL-1β, TNF-α, IL-6. Simultaneously, the inhibitory effects of HG on insulin-triggered glucose uptake and nephrin expression were overturned after celastrol exposure. Intriguingly, celastrol restored HG-induced deficiency of autophagy pathway. Nevertheless, blocking the autophagy signaling by its antagonist 3-MA muted celastrol-protected against HG-evoked cell injury, inflammation and insulin resistance. Importantly, celastrol enhanced heme oxygenase-1 (HO-1) expression in HG-stimulated podocytes. Notably, HO-1 cessation depressed autophagy pathway activation and subsequently blunted beneficial effects of celastrol on HG-exposed podocytes. These finding suggest that celastrol may protect against HG-induced podocyte injury, inflammation and insulin resistance by restoring HO-1-mediated autophagy pathway, implying a promising therapeutic strategy against DN.
糖尿病肾病 (DN) 可导致终末期肾病和肾功能障碍，其特征为足细胞损伤。炎症和胰岛素抵抗最近被认为与糖尿病肾病损伤的发病机制有关。雷公藤红素在炎症性疾病和损伤进展中发挥着重要作用。然而，其在 DN 中的功能和机制仍不清楚。在这里，雷公藤红素在高糖 (HG) 条件下剂量依赖性地恢复了足细胞的活力，而对足细胞的细胞毒性很小。雷公藤红素预处理可对抗 HG 诱导的细胞凋亡、LDH 释放、ROS 产生和足细胞耗竭。此外，HG 升高的促炎细胞因子的高转录和分泌在雷公藤红素治疗后得到逆转，包括 IL-1β、TNF-α、IL-6。同时，HG 对胰岛素触发的葡萄糖摄取和nephrin 表达的抑制作用在雷公藤红素暴露后被逆转。有趣的是，雷公藤红素恢复了 HG 诱导的自噬途径缺陷。然而，通过其拮抗剂 3-MA 阻断自噬信号，可使雷公藤红素对 HG 诱导的细胞损伤、炎症和胰岛素抵抗的保护作用减弱。重要的是，雷公藤红素增强了 HG 刺激的足细胞中血红素加氧酶-1 (HO-1) 的表达。值得注意的是，HO-1 的停止抑制了自噬途径的激活，随后削弱了雷公藤红素对 HG 暴露的足细胞的有益作用。这些发现表明，雷公藤红素通过恢复 HO-1 介导的自噬途径来防止 HG 诱导的足细胞损伤、炎症和胰岛素抵抗，为防治 DN 提供了一种有前景的治疗策略。
