Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, No. 318 Renmin Middle Road, 510623, Guangzhou city, China.
Pediatric Intensive Care Unit Department, The First People's Hospital of Zhaoqing, 526000, Zhaoqing city, China.
Lipids Health Dis. 2022 Apr 10;21(1):38. doi: 10.1186/s12944-022-01632-y.
It is unclear why primary nephrotic syndrome (PNS) patients often have dyslipidemia. Recent studies have shown that angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipid metabolism. In this study, we explored how ANGPTL3 impacts dyslipidemia during PNS development.
We measured the serum levels of ANGPTL3 in PNS patients (n=196). Furthermore, the degree of proteinuria and lipid metabolism were examined in angptl3-overexpressing transgenic (angptl3-tg) mice at different ages. Moreover, in this study, we used the clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system to create angptl3-knockout (angptl3-/-) mice to investigate lipopolysaccharide (LPS)-induced nephrosis.
Compared with that in the healthy group, the serum level of ANGPTL3 in the PNS group was significantly increased (32 (26.35-39.66) ng/ml vs. 70.44 (63.95-76.51) ng/ml, Z =-4.81, P < 0.001). There were significant correlations between the serum level of ANGPTL3 and the levels of cholesterol (r=0.34, P < 0.001), triglycerides (r= 0.25, P = 0.001) and low-density lipoprotein (r= 0.50, P < 0.001) in PNS patients. With increasing age, angptl3-tg mice exhibited increasingly severe hypertriglyceridemia and proteinuria. The pathological features of angptl3-tg mice included rich lipid droplet deposition in hepatocytes and diffuse podocyte effacement. Compared to wild-type mice, angptl3-/- mice showed significantly lower degrees of lipid dysfunction and proteinuria after stimulation with LPS. The effects of ANGPTL3 on nephrotic dyslipidemia were confirmed in cultured hepatocytes subjected to angptl3 knockdown or overexpression. Finally, significant alterations in lipoprotein lipase (LPL) levels were observed in liver tissues from Angptl3-/- and wild-type mice stimulated with LPS.
ANGPTL3 could be involved in the development of dyslipidemia, as well as proteinuria, during PNS pathogenesis. Inhibition of LPL expression may the mechanism by which ANGPTL3 induces hyperlipidemia in PNS.
原发性肾病综合征（PNS）患者常伴有血脂异常，但具体原因尚不清楚。最近的研究表明，血管生成素样蛋白 3（ANGPTL3）是脂质代谢的重要调节因子。本研究旨在探讨 ANGPTL3 如何影响 PNS 发展过程中的血脂异常。
我们测量了 196 例 PNS 患者的血清 ANGPTL3 水平。此外，在不同年龄阶段，我们观察了过表达 ANGPTL3 的转基因（angptl3-tg）小鼠的蛋白尿和脂质代谢程度。此外，我们还使用了规律成簇间隔短回文重复序列相关蛋白 9（CRISPR/Cas9）系统来创建 angptl3 敲除（angptl3-/-）小鼠，以研究脂多糖（LPS）诱导的肾病。
与健康组相比，PNS 组患者的血清 ANGPTL3 水平显著升高（32（26.35-39.66）ng/ml 比 70.44（63.95-76.51）ng/ml，Z=-4.81，P<0.001）。在 PNS 患者中，血清 ANGPTL3 水平与胆固醇（r=0.34，P<0.001）、甘油三酯（r=0.25，P=0.001）和低密度脂蛋白（r=0.50，P<0.001）水平呈显著正相关。随着年龄的增长，angptl3-tg 小鼠表现出越来越严重的高甘油三酯血症和蛋白尿。angptl3-tg 小鼠的病理特征包括肝细胞内富含脂质滴沉积和弥漫性足细胞足突融合。与野生型小鼠相比，LPS 刺激后 angptl3-/-小鼠的脂质功能障碍和蛋白尿程度明显降低。在经 ANGPTL3 敲低或过表达处理的培养肝细胞中，证实了 ANGPTL3 对肾病性血脂异常的影响。最后，在 LPS 刺激的 Angptl3-/-和野生型小鼠的肝组织中观察到脂蛋白脂肪酶（LPL）水平的显著变化。
ANGPTL3 可能参与了 PNS 发病过程中蛋白尿和血脂异常的发生。抑制 LPL 表达可能是 ANGPTL3 诱导 PNS 高脂血症的机制。
