Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.
Department of Traditional Chinese Medicine, Children's Hospital of Fudan University, Shanghai, China.
Int Immunopharmacol. 2023 Feb;115:109656. doi: 10.1016/j.intimp.2022.109656. Epub 2023 Jan 4.
Minimal change disease (MCD) is the common type of nephrotic syndrome in children. There is an urgent need to explore new treatment methods as current treatments have many drawbacks and cause significant side effects. Our group found that Angiopoietin-like protein 3 (Angptl3) is closely related to renal disease and Angptl3 knockout significantly alleviated proteinuria in mice with adriamycin nephropathy (AN), however, some proteinuria was still present. Minnelide is a water-soluble prodrug of triptolide which has been used for the treatment of glomerular diseases. Therefore, this study aimed to investigate whether minnelide, combined with Angptl3 knockout, could completely protect mice with AN and its mechanism. AN was induced in B6;129S5 female mice by tail vein injection of 25 mg/kg of Adriamycin (ADR), and treatment with 200 ug/kg/d of minnelide. The results showed that minnelide combined with Angptl3 knockout completely reduced proteinuria and restored the foot processes in mice with AN. Moreover, in Angptl3 knockout mice with AN, minnelide restored the distribution of nephrin, podocin and cd2ap and reduced inflammatory factors (Tumor necrosis factor alpha (TNF-α), Interleukin-6 (IL-6) and Interleukin-1β (IL-1β)). Through RNA sequencing and related experiments, we found minnelide could ameliorate fibrosis and apoptosis by inhibiting TGF-β1-Smad2 and p53 pathways in Angptl3 knockout mice with AN, respectively. In Angptl3 knockout primary podocytes, triptolide alleviates ADR-induced decreases in nephrin, podocin and cd2ap, upregulation of Bax and downregulation of Bcl-2. Overall, our study shows that minnelide combined with Angptl3 knockout completely protects mice with AN by inhibiting the TGF-β1-smad2 and p53 pathways.
微小病变病（MCD）是儿童肾病综合征的常见类型。由于目前的治疗方法存在许多缺点并会引起明显的副作用，因此迫切需要探索新的治疗方法。我们小组发现血管生成素样蛋白 3（Angptl3）与肾脏疾病密切相关，Angptl3 基因敲除可显著减轻阿霉素肾病（AN）小鼠的蛋白尿，但仍存在一些蛋白尿。米内利德是雷公藤内酯醇的水溶性前体药物，已用于治疗肾小球疾病。因此，本研究旨在探讨米内利德联合 Angptl3 基因敲除是否能完全保护 AN 小鼠及其机制。通过尾静脉注射 25mg/kg 阿霉素（ADR）诱导 B6;129S5 雌性小鼠发生 AN，并给予 200ug/kg/d 米内利德治疗。结果表明，米内利德联合 Angptl3 基因敲除可完全减少蛋白尿并恢复 AN 小鼠的足突。此外，在 AN 中 Angptl3 基因敲除的小鼠中，米内利德恢复了 Nephrin、Podocin 和 CD2AP 的分布，并减少了炎症因子（肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β））。通过 RNA 测序和相关实验，我们发现米内利德可通过抑制 TGF-β1-Smad2 和 p53 通路分别改善 Angptl3 基因敲除的 AN 小鼠的纤维化和细胞凋亡。在 Angptl3 基因敲除的原代足细胞中，雷公藤内酯醇可减轻 ADR 诱导的 Nephrin、Podocin 和 CD2AP 减少、Bax 上调和 Bcl-2 下调。总之，本研究表明米内利德联合 Angptl3 基因敲除可通过抑制 TGF-β1-smad2 和 p53 通路完全保护 AN 小鼠。
