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2016 ; 11
(2
): e0150083
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Lipoprotein X Causes Renal Disease in LCAT Deficiency
#MMPMID26919698
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
PLoS One
2016[]; 11
(2
): e0150083
PMID26919698
show ga
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.
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