ANGPLT3 Impacts Proteinuria and Hyperlipidemia in Primary Nephrotic Syndrome

Background: 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 in PNS development. Methods: We measured the serum levels of ANGPTL3 in PNS patients. Furthermore, the degree of proteinuria and lipid metabolism were examined in angptl3-overexpressing transgenic (angptl3-tg) mice at different weeks of age. Moreover, this study used the clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system to create angptl3-knockout (angptl3-/-) mice to observe lipopolysaccharide (LPS)-induced nephrotic mice. Results: There was a significant correlation between the serum level of ANGPTL3 and the levels of cholesterol, triglycerides and low-density lipoprotein in PNS patients. With increasing age, angptl3-tg mice exhibited increasingly severe hypertriglyceridemia and proteinuria. The pathological features included rich lipid droplet deposition in hepatocytes and diffuse podocyte effacement in angptl3-tg mice. 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 with angptl3 knockdown or overexpression. Finally, significant alterations in lipoprotein lipase (LPL) were observed in liver tissues from Angptl3-/- and wild-type mice stimulated with LPS. Conclusion: ANGPTL3 could be involved in the development of dyslipidemia, as well as proteinuria, in PNS pathogenesis. Inhibiting LPL expression may be why ANGPTL3 induces hyperlipidemia in PNS.