肾小球足细胞损伤，涉及肾小球上皮间充质转化过程 (EMT)，是糖尿病肾病 (DN) 和蛋白尿进展的关键因素。本研究旨在研究血管生成抑制素样蛋白3 (Angptl3) 敲除在 DN 小鼠和 HG 处理的肾小球损伤和巨噬细胞极化中的保护性。此外，我们还试图研究背后的分子机制负责这些效应。DN 通过腹腔注射 40 mg/kg 链脲佐菌素 (STZ) 在 B6;129S5 小鼠中诱导。随后，评估了肾功能、肾小球凋亡、炎症因子 (肿瘤坏死因子-α [TNF-α]、白细胞介素-6 [IL-6]、白细胞介素-1β [IL-1β]、IL-10、TGF-β1、IL-1Ra 、IL-10Ra 和 nephrin 的变化。此外，我们还调查了 Angptl3 在巨噬细胞极化、肾小球损伤和肾小球 EMT 中的作用机制。研究结果显示，Angptl3 敲除显著减轻了 STZ 或 HG 诱导的肾功能障碍和肾小球 EMT。在体内和体外研究中，Angptl3 敲除导致：(1) 促进 M1 类巨噬细胞向 M2 类巨噬细胞的转化；(2) 缓解 nephrin、synaptopodin 和 podocin 的表达下降；(3) 抑制 NLRP3 气孔体的激活和 IL-1β 的释放；以及 (4) 通过巨噬细胞极化调节 α-SMA 的表达。(5) HG 处理后，出现了炎症因子的增加和足细胞损伤。这些变化在 Angptle 敲除后被逆转。我们的研究表明，Angptl3 敲除通过调节巨噬细胞极化缓解了肾小球 EMT 和肾小球损伤。Copyright © 2023 Ma, Chen, Xu and Du.

Podocyte injury, which involves the podocyte epithelial-mesenchymal transition (EMT) process, is a crucial factor contributing to the progression of diabetic nephropathy (DN) and proteinuria. Our study aimed to examine the protective properties of Angiopoietin-like protein 3 (Angptl3) knockout on podocyte damage and macrophage polarization in DN mice and podocytes treated with HG. Furthermore, we also sought to investigate the underlying molecular mechanism responsible for these effects.DN was induced in B6;129S5 mice through intraperitoneal injection of 40 mg/kg of streptozotocin (STZ). Subsequently, the changes in renal function, podocyte apoptosis, inflammatory factors (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]), IL-10, TGF-β1, IL-1Ra, IL-10Ra, and nephrin were evaluated. Moreover, we investigated the mechanism underlying the role of Angptl3 in macrophages polarization, podocyte injury, podocyte EMT.Our findings revealed that Angptl3 knockout significantly attenuated STZ or HG-induced renal dysfunction and podocyte EMT. In both in vivo and in vitro studies, Angptl3 knockout led to (1) promote the transformation of M1 type macrophages into M2 type macrophages; (2) amelioration of the reduced expression of nephrin, synaptopodin, and podocin; (3) inhibition of NLRP3 inflammasome activation and release of IL-1β; and (4) regulation of α-SMA expression via the macrophage polarization. (5) After HG treatment, there was an increase in pro-inflammatory factors and foot cell damage. These changes were reversed upon Angptle knockdown.Our study suggests that the knockout of Angptl3 alleviates podocyte EMT and podocyte injury by regulating macrophage polarization.Copyright © 2023 Ma, Chen, Xu and Du.