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2020 ; 15
(2
): e0228938
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Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A,
magnesium and pyrophosphate
#MMPMID32074140
Babler A
; Schmitz C
; Buescher A
; Herrmann M
; Gremse F
; Gorgels T
; Floege J
; Jahnen-Dechent W
PLoS One
2020[]; 15
(2
): e0228938
PMID32074140
show ga
Calcifications can disrupt organ function in the cardiovascular system and the
kidney, and are particularly common in patients with chronic kidney disease
(CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2
exhibit particularly severe soft tissue calcifications, while fetuin-A deficient
C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify
risk factors of calcification in fetuin-A deficient mice. We sought to identify
pharmaceutical therapeutic targets that could be influenced by dietary of
parenteral supplementation. We studied the progeny of an intercross of fetuin-A
deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in
calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a
liver ATP transporter supplying systemic pyrophosphate, and failure to regulate
the Trpm6 magnesium transporter in kidney were associated with severity of
calcification. Calcification prone fetuin-A deficient mice were alternatively
treated with parenteral administration of fetuin-A dietary magnesium
supplementation, phosphate restriction, or by or parenteral pyrophosphate. All
treatments markedly reduced soft tissue calcification, demonstrated by computed
tomography, histology and tissue calcium measurement. We show that pathological
ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound
deficiency of three major extracellular and systemic inhibitors of calcification,
namely fetuin-A, magnesium, and pyrophosphate. All three of these are
individually known to contribute to stabilize protein-mineral complexes and thus
inhibit mineral precipitation from extracellular fluid. We show for the first
time a compound triple deficiency that can be treated by simple dietary or
parenteral supplementation. This is of special importance in patients with
advanced CKD, who commonly exhibit reduced serum fetuin-A, magnesium and
pyrophosphate levels.
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