Lipoprotein X Causes Renal Disease in LCAT Deficiency.
Lipoprotein X Causes Renal Disease in LCAT Deficiency.
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DOI：
10.1371/journal.pone.0150083
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Remaley AT
中科院分区：
文献类型：
--
作者：
Ossoli A;Neufeld EB;Thacker SG;Vaisman B;Pryor M;Freeman LA;Brantner CA;Baranova I;Francone NO;Demosky SJ Jr;Vitali C;Locatelli M;Abbate M;Zoja C;Franceschini G;Calabresi L;Remaley AT
人类家族性卵磷脂：胆固醇酰基转移酶（LCAT）缺乏症（FLD）的特征是低HDL，血浆中异常富含胆固醇的多层颗粒（称为脂蛋白-X（LpX））的积累和肾脏疾病。本研究的目的是确定LpX是否具有肾毒性，并深入了解FLD肾病的发病机制。我们给野生型和Lcat-/-小鼠施用了一种合成的LpX，其物理、化学和生物学特性与内源性LpX几乎相同。我们的体外和体内研究表明，apoA-I和LCAT依赖性途径LpX转化为HDL样颗粒，这可能介导LpX的正常血浆清除。外源性LpX的血浆清除率在Lcat-/-小鼠中显著延迟，Lcat-/-小鼠具有低HDL，但仅具有最少量的内源性LpX，并且不会自发地发展为肾脏疾病。长期给予外源性LpX沉积在Lcat-/-小鼠的所有肾小球细胞和基质隔室中，并诱导蛋白尿和肾毒性基因变化，以及通过组织学、TEM和SEM分析评估的FLD肾病的所有标志。广泛的体内EM研究显示，LpX通过巨胞饮作用摄取到小鼠肾小球内皮细胞、足细胞和系膜细胞中，并递送到溶酶体中降解。内吞的LpX似乎被人足细胞和系膜细胞溶酶体PLA 2降解，并诱导足细胞分泌促炎性IL-6（体外）和Lcat-/-小鼠肾脏Cxl 10表达。总之，LpX是一种肾毒性颗粒，在不存在Lcat的情况下诱导FLD的所有组织学和功能标志，因此可以作为监测重组LCAT治疗的生物标志物。此外，我们的研究表明，LpX诱导的内皮屏障功能丧失和肾小球细胞释放细胞因子可能在FLD肾病的发生和发展中起作用。
Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, chemical and biologic characteristics, to wild-type and Lcat-/- mice. Our in vitro and in vivo studies demonstrated an apoA-I and LCAT-dependent pathway for LpX conversion to HDL-like particles, which likely mediates normal plasma clearance of LpX. Plasma clearance of exogenous LpX was markedly delayed in Lcat-/- mice, which have low HDL, but only minimal amounts of endogenous LpX and do not spontaneously develop renal disease. Chronically administered exogenous LpX deposited in all renal glomerular cellular and matrical compartments of Lcat-/- mice, and induced proteinuria and nephrotoxic gene changes, as well as all of the hallmarks of FLD renal disease as assessed by histological, TEM, and SEM analyses. Extensive in vivo EM studies revealed LpX uptake by macropinocytosis into mouse glomerular endothelial cells, podocytes, and mesangial cells and delivery to lysosomes where it was degraded. Endocytosed LpX appeared to be degraded by both human podocyte and mesangial cell lysosomal PLA2 and induced podocyte secretion of pro-inflammatory IL-6 in vitro and renal Cxl10 expression in Lcat-/- mice. In conclusion, LpX is a nephrotoxic particle that in the absence of Lcat induces all of the histological and functional hallmarks of FLD and hence may serve as a biomarker for monitoring recombinant LCAT therapy. In addition, our studies suggest that LpX-induced loss of endothelial barrier function and release of cytokines by renal glomerular cells likely plays a role in the initiation and progression of FLD nephrosis.