TY - JOUR
T1 - PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet
AU - Yamada, Shunsuke
AU - Leaf, Elizabeth M.
AU - Chia, Jia Jun
AU - Cox, Timothy C.
AU - Speer, Mei Y.
AU - Giachelli, Cecilia M.
N1 - Funding Information:
CMG is supported by grants from the National Institutes of Health (HL62329, HL081785, and HL114611) and the Department of Defense (OR120074). SY is supported by grants from the Japanese Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad (JSPS 20150701) and the Uehara Memorial Foundation 2017.
Funding Information:
CMG is supported by grants from the National Institutes of Health (HL62329, HL081785, and HL114611) and the Department of Defense (OR120074). SY is supported by grants from the Japanese Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad (JSPS 20150701) and the Uehara Memorial Foundation 2017.
Publisher Copyright:
© 2018 International Society of Nephrology
PY - 2018/10
Y1 - 2018/10
N2 - PiT-2, a type III sodium-dependent phosphate transporter, is a causative gene for the brain arteriolar calcification in people with familial basal ganglion calcification. Here we examined the effect of PiT-2 haploinsufficiency on vascular calcification in uremic mice using wild-type and global PiT-2 heterozygous knockout mice. PiT-2 haploinsufficiency enhanced the development of vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. No differences were observed in the serum mineral biomarkers and kidney function between the wild-type and PiT-2 heterozygous knockout groups. Micro computed tomography analyses of femurs showed that haploinsufficiency of PiT-2 decreased trabecular bone mineral density in uremia. In vitro, sodium-dependent phosphate uptake was decreased in cultured vascular smooth muscle cells isolated from PiT-2 heterozygous knockout mice compared with those from wild-type mice. PiT-2 haploinsufficiency increased phosphate-induced calcification of cultured vascular smooth muscle cells compared to the wild-type. Furthermore, compared to wild-type vascular smooth muscle cells, PiT-2 deficient vascular smooth muscle cells had lower osteoprotegerin levels and increased matrix calcification, which was attenuated by osteoprotegerin supplementation. Thus, PiT-2 in vascular smooth muscle cells protects against phosphate-induced vascular calcification and may be a therapeutic target in the chronic kidney disease population.
AB - PiT-2, a type III sodium-dependent phosphate transporter, is a causative gene for the brain arteriolar calcification in people with familial basal ganglion calcification. Here we examined the effect of PiT-2 haploinsufficiency on vascular calcification in uremic mice using wild-type and global PiT-2 heterozygous knockout mice. PiT-2 haploinsufficiency enhanced the development of vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. No differences were observed in the serum mineral biomarkers and kidney function between the wild-type and PiT-2 heterozygous knockout groups. Micro computed tomography analyses of femurs showed that haploinsufficiency of PiT-2 decreased trabecular bone mineral density in uremia. In vitro, sodium-dependent phosphate uptake was decreased in cultured vascular smooth muscle cells isolated from PiT-2 heterozygous knockout mice compared with those from wild-type mice. PiT-2 haploinsufficiency increased phosphate-induced calcification of cultured vascular smooth muscle cells compared to the wild-type. Furthermore, compared to wild-type vascular smooth muscle cells, PiT-2 deficient vascular smooth muscle cells had lower osteoprotegerin levels and increased matrix calcification, which was attenuated by osteoprotegerin supplementation. Thus, PiT-2 in vascular smooth muscle cells protects against phosphate-induced vascular calcification and may be a therapeutic target in the chronic kidney disease population.
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U2 - 10.1016/j.kint.2018.05.015
DO - 10.1016/j.kint.2018.05.015
M3 - Article
C2 - 30041812
AN - SCOPUS:85050119335
VL - 94
SP - 716
EP - 727
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 4
ER -