Sodium-Dependent Phosphate Cotransporters and Phosphate-Induced Calcification of Vascular Smooth Muscle Cells

Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 33 Số 11 - Trang 2625-2632 - 2013
Matthew H. Crouthamel1, Wei Ling Lau1, Elizabeth M. Leaf1, Nicholas W. Chavkin1, Mary C. Wallingford1, Danielle F. Peterson1, Xianwu Li1, Yonggang Liu1, Michael T. Chin1, Moshe Levi1, Cecilia M. Giachelli1
1From the Departments of Bioengineering (M.H.C., E.M.L., N.W.C., M.C.W., D.F.P., X.L., C.M.G.), Nephrology (W.L.L.), and Cardiology (Y.L., M.T.C.), University of Washington, Seattle; and Department of Medicine, University of Colorado, Denver (M.L.).

Tóm tắt

Objective— Elevated serum phosphate has emerged as a major risk factor for vascular calcification. The sodium-dependent phosphate cotransporter, PiT-1, was previously shown to be required for phosphate-induced osteogenic differentiation and calcification of cultured human vascular smooth muscle cells (VSMCs), but its importance in vascular calcification in vivo and the potential role of its homologue, PiT-2, have not been determined. We investigated the in vivo requirement for PiT-1 in vascular calcification using a mouse model of chronic kidney disease and the potential compensatory role of PiT-2 using in vitro knockdown and overexpression strategies. Approach and Results— Mice with targeted deletion of PiT-1 in VSMCs were generated (PiT-1 Δ sm ). PiT-1 mRNA levels were undetectable, whereas PiT-2 mRNA levels were increased 2-fold in the vascular aortic media of PiT-1 Δsm compared with PiT-1 flox/flox control. When arterial medial calcification was induced in PiT-1 Δsm and PiT-1 flox/flox by chronic kidney disease followed by dietary phosphate loading, the degree of aortic calcification was not different between genotypes, suggesting compensation by PiT-2. Consistent with this possibility, VSMCs isolated from PiT-1 Δsm mice had no PiT-1 mRNA expression, increased PiT-2 mRNA levels, and no difference in sodium-dependent phosphate uptake or phosphate-induced matrix calcification compared with PiT-1 flox/flox VSMCs. Knockdown of PiT-2 decreased phosphate uptake and phosphate-induced calcification of PiT-1 Δsm VSMCs. Furthermore, overexpression of PiT-2 restored these parameters in human PiT-1–deficient VSMCs. Conclusions— PiT-2 can mediate phosphate uptake and calcification of VSMCs in the absence of PiT-1. Mechanistically, PiT-1 and PiT-2 seem to serve redundant roles in phosphate-induced calcification of VSMCs.

Từ khóa


Tài liệu tham khảo

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Arteriosclerosis, Thrombosis, and Vascular Biology

Tập 33 Số 11

2625-2632

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