Phosphate uptake-independent signaling functions of the type III sodium-dependent phosphate transporter, PiT-1, in vascular smooth muscle cells.
Phosphate uptake-independent signaling functions of the type III sodium-dependent phosphate transporter, PiT-1, in vascular smooth muscle cells.
复制标题
DOI：
10.1016/j.yexcr.2015.02.002
复制
发表时间：
2015-04-10
影响因子：
3.7
通讯作者：
Giachelli, Cecilia M.
中科院分区：
文献类型：
--
作者：
Chavkin, Nicholas W.;Chia, Jia Jun;Crouthamel, Matthew H.;Giachelli, Cecilia M.
血管钙化（VC）在慢性肾脏疾病中普遍存在，血清无机磷（Pi）升高是公认的风险因素。III型钠依赖性磷酸盐转运蛋白PiT-1是血管平滑肌细胞（VSMC）中Pi诱导的骨软骨分化和基质矿化升高所必需的。然而，PiT-1促进这些过程的分子机制尚不清楚。在本研究中，我们证实了诱导小鼠VSMCs骨软骨分化和基质矿化所需的Pi浓度远高于最大Pi摄取所需的浓度，表明PiT-1的信号传导功能独立于Pi的转运。在PiT-1缺陷型VSMC中，通过ERK 1/2磷酸化增强的Pi诱导信号传导被消除，但可以被野生型（WT）和Pi转运缺陷型PiT-1突变体拯救。此外，WT和转运缺陷型PiT-1突变体均促进骨软骨形成分化，表现为SM 22 α表达降低和骨桥蛋白mRNA表达增加。最后，与单独的载体相比，转运缺陷型PiT-1突变体的表达促进了VSMC基质矿化，但没有达到PiT-1 WT所观察到的程度。这些数据表明，这两个Pi摄取依赖性和非依赖性功能的PiT-1是重要的VSMC过程介导的血管钙化。
Vascular calcification (VC) is prevalent in chronic kidney disease and elevated serum inorganic phosphate (Pi) is a recognized risk factor. The type III sodium-dependent phosphate transporter, PiT-1, is required for elevated Pi-induced osteochondrogenic differentiation and matrix mineralization in vascular smooth muscle cells (VSMCs). However, the molecular mechanism(s) by which PiT-1 promotes these processes is unclear. In the present study, we confirmed that the Pi concentration required to induce osteochondrogenic differentiation and matrix mineralization of mouse VSMCs was well above that required for maximal Pi uptake, suggesting a signaling function of PiT-1 that was independent of Pi transport. Elevated Pi-induced signaling via ERK1/2 phosphorylation was abrogated in PiT-1 deficient VSMCs, but could be rescued by wild-type (WT) and a Pi transport-deficient PiT-1 mutant. Furthermore, both WT and transport-deficient PiT-1 mutants promoted osteochondrogenic differentiation as measured by decreased SM22α and increased osteopontin mRNA expression. Finally, compared to vector alone, expression of transport-deficient PiT-1 mutants promoted VSMC matrix mineralization, but not to the extent observed with PiT-1 WT. These data suggest that both Pi uptake-dependent and -independent functions of PiT-1 are important for VSMC processes mediating vascular calcification.
登录
查看更多内容
影响因子：
20.1
作者：
Li, XW;Yang, HY;Giachelli, CM
通讯作者：
Giachelli, CM
影响因子：
37.8
作者：
Shroff, Rukshana C.;McNair, Rosamund;Shanahan, Catherine M.
通讯作者：
Shanahan, Catherine M.
影响因子：
4.1
作者：
Kimata, Masaaki;Michigami, Toshimi;Ozono, Keiichi
通讯作者：
Ozono, Keiichi
影响因子：
158.5
作者：
Detrano, Robert;Guerci, Alan D.;Kronmal, Richard A.
通讯作者：
Kronmal, Richard A.
影响因子：
4.8
作者：
Salauen, Christine;Leroy, Christine;Friedlander, Gerard
通讯作者：
Friedlander, Gerard