前蛋白转化酶枯草溶菌素/克新9型在肾病综合征相关高胆固醇血症中的作用
The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia.
作者信息
Haas Mary E, Levenson Amy E, Sun Xiaowei, Liao Wan-Hui, Rutkowski Joseph M, de Ferranti Sarah D, Schumacher Valerie A, Scherer Philipp E, Salant David J, Biddinger Sudha B
机构信息
From Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
出版信息
Circulation. 2016 Jul 5;134(1):61-72. doi: 10.1161/CIRCULATIONAHA.115.020912.
BACKGROUND
In nephrotic syndrome, damage to the podocytes of the kidney produces severe hypercholesterolemia for which novel treatments are urgently needed. PCSK9 (proprotein convertase subtilisin/kexin type 9) has emerged as an important regulator of plasma cholesterol levels and therapeutic target. Here, we tested the role of PCSK9 in mediating the hypercholesterolemia of nephrotic syndrome.
METHODS
PCSK9 and plasma lipids were studied in nephrotic syndrome patients before and after remission of disease, mice with genetic ablation of the podocyte (Podocyte Apoptosis Through Targeted Activation of Caspase-8, Pod-ATTAC mice) and mice treated with nephrotoxic serum (NTS), which triggers immune-mediated podocyte damage. In addition, mice with hepatic deletion of Pcsk9 were treated with NTS to determine the contribution of PCSK9 to the dyslipidemia of nephrotic syndrome.
RESULTS
Patients with nephrotic syndrome showed a decrease in plasma cholesterol and plasma PCSK9 on remission of their disease (P<0.05, n=47-50). Conversely, Pod-ATTAC mice and NTS-treated mice showed hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9. The induction of plasma PCSK9 appeared to be attributable to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Interestingly, knockout of Pcsk9ameliorated the effects of NTS on plasma lipids. Thus, in the presence of NTS, mice lacking hepatic Pcsk9 showed a 40% to 50% decrease in plasma cholesterol and triglycerides. Moreover, the ability of NTS treatment to increase the percentage of low-density lipoprotein-associated cholesterol (from 9% in vehicle-treated Flox mice to 47% after NTS treatment), was lost in mice with hepatic deletion of Pcsk9 (5% in both the presence and absence of NTS).
CONCLUSIONS
Podocyte damage triggers marked inductions in plasma PCSK9, and knockout of Pcsk9 ameliorates dyslipidemia in a mouse model of nephrotic syndrome. These data suggest that PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome-associated hypercholesterolemia.
背景
在肾病综合征中，肾脏足细胞损伤会导致严重的高胆固醇血症，迫切需要新的治疗方法。前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）已成为血浆胆固醇水平的重要调节因子和治疗靶点。在此，我们测试了PCSK9在介导肾病综合征高胆固醇血症中的作用。
方法
对肾病综合征患者疾病缓解前后的PCSK9和血脂进行研究，对足细胞基因敲除小鼠（通过靶向激活半胱天冬酶-8诱导足细胞凋亡的小鼠，Pod-ATTAC小鼠）和用肾毒性血清（NTS）处理的小鼠进行研究，NTS可引发免疫介导的足细胞损伤。此外，对肝脏缺失Pcsk9的小鼠用NTS处理，以确定PCSK9对肾病综合征血脂异常的影响。
结果
肾病综合征患者疾病缓解后血浆胆固醇和血浆PCSK9降低（P<0.05，n = 47 - 50）。相反，Pod-ATTAC小鼠和NTS处理的小鼠表现出高胆固醇血症，血浆PCSK9诱导7至24倍。血浆PCSK9的诱导似乎归因于肝细胞PCSK9分泌增加以及清除减少。有趣的是，敲除Pcsk9可改善NTS对血脂的影响。因此，在存在NTS的情况下，肝脏缺失Pcsk9的小鼠血浆胆固醇和甘油三酯降低40%至50%。此外，NTS处理增加低密度脂蛋白相关胆固醇百分比的能力（从载体处理的Flox小鼠中的9%增加到NTS处理后的47%），在肝脏缺失Pcsk9的小鼠中丧失（无论有无NTS均为5%）。
结论
足细胞损伤会引发血浆PCSK9显著诱导，敲除Pcsk9可改善肾病综合征小鼠模型的血脂异常。这些数据表明PCSK9抑制剂可能对肾病综合征相关高胆固醇血症患者有益。
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