Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
The Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Organogenesis. 2024 Dec 31;20(1):2356339. doi: 10.1080/15476278.2024.2356339. Epub 2024 May 26.
This study is to investigate the therapeutical effect and mechanisms of human-derived adipose mesenchymal stem cells (ADSC) in relieving adriamycin (ADR)-induced nephropathy (AN). SD rats were separated into normal group, ADR group, ADR+Losartan group (20 mg/kg), and ADR + ADSC group. AN rats were induced by intravenous injection with adriamycin (8 mg/kg), and 4 d later, ADSC (2 × 10 cells/mouse) were administrated twice with 2 weeks interval time (i.v.). The rats were euthanized after the 6 weeks' treatment. Biochemical indicators reflecting renal injury, such as blood urea nitrogen (BUN), neutrophil gelatinase alpha (NGAL), serum creatinine (Scr), inflammation, oxidative stress, and pro-fibrosis molecules, were evaluated. Results demonstrated that we obtained high qualified ADSCs for treatment determined by flow cytometry, and ADSCs treatment significantly ameliorated renal injuries in DN rats by decreasing BUN, Scr and NGAL in peripheral blood, as well as renal histopathological injuries, especially protecting the integrity of podocytes by immunofluorescence. Furthermore, ADSCs treatment also remarkably reduced the renal inflammation, oxidative stress, and fibrosis in DN rats. Preliminary mechanism study suggested that the ADSCs treatment significantly increased renal neovascularization via enhancing proangiogenic VEGF production. Pharmacodynamics study using in vivo imaging confirmed that ADSCs via intravenous injection could accumulate into the kidneys and be alive at least 2 weeks. In a conclusion, ADSC can significantly alleviate ADR-induced nephropathy, and mainly through reducing oxidative stress, inflammation and fibrosis, as well as enhancing VEGF production.
本研究旨在探讨人源脂肪间充质干细胞（ADSC）缓解阿霉素（ADR）诱导的肾病（AN）的治疗作用和机制。SD 大鼠分为正常组、ADR 组、ADR+氯沙坦组（20mg/kg）和 ADR+ADSC 组。通过静脉注射阿霉素（8mg/kg）诱导 AN 大鼠，4 天后，每隔 2 周通过静脉注射（i.v.）两次给予 2×10 个细胞/只 ADSC。治疗 6 周后处死大鼠。评估反映肾损伤的生化指标，如血尿素氮（BUN）、中性粒细胞明胶酶相关载脂蛋白（NGAL）、血清肌酐（Scr）、炎症、氧化应激和促纤维化分子。结果表明，我们通过流式细胞术获得了用于治疗的高质量 ADSC，ADSC 治疗通过降低外周血中 BUN、Scr 和 NGAL 以及肾组织病理学损伤，显著改善了糖尿病肾病大鼠的肾损伤，特别是通过免疫荧光法保护足细胞的完整性。此外，ADSC 治疗还显著降低了糖尿病肾病大鼠的肾脏炎症、氧化应激和纤维化。初步的机制研究表明，ADSC 治疗通过增强促血管生成 VEGF 的产生，显著增加了肾脏的新生血管。体内成像的药效学研究证实，ADSC 通过静脉注射可以积聚到肾脏并至少存活 2 周。综上所述，ADSC 可显著缓解 ADR 诱导的肾病，主要通过减轻氧化应激、炎症和纤维化，以及增强 VEGF 的产生。
