Department of Pediatrics, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.
Front Immunol. 2023 Aug 10;14:1228399. doi: 10.3389/fimmu.2023.1228399. eCollection 2023.
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 and 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.
足细胞损伤涉及足细胞上皮-间充质转化（EMT）过程，是导致糖尿病肾病（DN）和蛋白尿进展的关键因素。我们的研究旨在探讨血管生成素样蛋白 3（Angptl3）敲除对 DN 小鼠和高糖（HG）处理的足细胞中足细胞损伤和巨噬细胞极化的保护作用，并进一步探讨其潜在的分子机制。
通过腹腔注射 40mg/kg 链脲佐菌素（STZ）诱导 B6；129S5 小鼠发生 DN。然后，评估肾功能、足细胞凋亡、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]）、IL-10、TGF-β1、IL-1Ra、IL-10Ra 和nephrin 的变化。此外，我们还研究了 Angptl3 在巨噬细胞极化、足细胞损伤、足细胞 EMT 中的作用机制。
我们的研究结果表明，Angptl3 敲除显著减轻了 STZ 或 HG 诱导的肾功能障碍和足细胞 EMT。在 和 研究中，Angptl3 敲除导致（1）促进 M1 型巨噬细胞向 M2 型巨噬细胞转化；（2）改善 nephrin、synaptopodin 和 podocin 的表达减少；（3）抑制 NLRP3 炎性小体的激活和 IL-1β 的释放；（4）通过巨噬细胞极化调节α-SMA 的表达。（5）HG 处理后，促炎因子增加，足细胞损伤。Angptl3 敲低后这些变化得到逆转。
我们的研究表明，Angptl3 敲除通过调节巨噬细胞极化缓解足细胞 EMT 和足细胞损伤。
