The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia.
The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia.
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DOI：
10.1161/circulationaha.115.020912
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发表时间：
2016-07-05
期刊：
影响因子：
37.8
通讯作者：
Biddinger SB
中科院分区：
文献类型：
--
作者：
Haas ME;Levenson AE;Sun X;Liao WH;Rutkowski JM;de Ferranti SD;Schumacher VA;Scherer PE;Salant DJ;Biddinger SB
在肾病综合征中，肾脏足细胞的损伤会导致严重的高胆固醇血症，迫切需要新的治疗方法。枯草杆菌前蛋白转换酶9(PCSK9)已成为血浆胆固醇水平的重要调节因子和治疗靶点。在这里，我们测试了PCSK9在介导肾病综合征高胆固醇血症中的作用。肾毒性血清(NTS)治疗导致足细胞免疫介导的损害，以及基因消融足细胞产生高胆固醇血症，并在小鼠血浆中诱导PCSK9的7-24倍。相反，肾病综合征患者在病情缓解后血浆胆固醇和PCSK9水平降低(p<；0.05，n=47-50)。肾病综合征患者血浆PCSK9的产生可能是由于肝细胞分泌PCSK9增加，清除率降低所致。有趣的是，敲除PCSK9可以改善NTS对血脂的影响。因此，在NTS存在的情况下，缺乏肝脏PCSK9的小鼠的血浆胆固醇和甘油三酯降低了40%到50%。此外，NTS治疗增加低密度脂蛋白相关胆固醇比例的能力(从赋形剂治疗的Flox小鼠的9%增加到NTS治疗后的47%)，在肝脏PCSK9缺失的小鼠中丧失(在存在和不存在NTS的情况下都是5%)。足细胞损伤触发血浆PCSK9的显著诱导，PCSK9基因敲除可改善肾病综合征小鼠模型的血脂紊乱。这些数据表明，PCSK9抑制剂对肾病综合征相关高胆固醇血症患者可能是有益的。
In nephrotic syndrome, damage to the podocytes of the kidney produces severe hypercholesterolemia for which novel treatments are urgently needed. Proprotein convertase subtilisin/kexin type 9 (PCSK9) 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. Both nephrotoxic serum (NTS) treatment, which induces immune-mediated damage of the podocyte, and genetic ablation of the podocyte produced hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9 in mice. Conversely, patients with nephrotic syndrome showed a decrease in plasma cholesterol and plasma PCSK9 upon remission of their disease (p<0.05, n=47-50). The induction of plasma PCSK9 in nephrotic syndrome appeared to be due to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Interestingly, knockout of Pcsk9 ameliorated 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 proportion of LDL-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). 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.