The long-term objective of this project is to delineate mechanisms of vascular calcification in patients with chronic kidney disease-mineral bone disorder (CKD-MBD). Vascular calcification is a major killer of CKD-MBD patients primarily through the heightened risk of cardiovascular morbidity and mortality. Elevated phosphate at levels of hyperphosphatemia has been identified as a key inducer of vascular calcification via procalcific effects on vascular smooth muscle cells (VSMC). In the previous funding period, we identified a novel function for the sodium dependent phosphate transporter, PiT-1, as a mediator of elevated-phosphate-induced vascular calcification in vitro and in vivo. Moreover, we provide mechanistic insight into compensatory mechanisms of the alternative family member, PiT-2, that operates in VSMC to protect against phosphate transporter deficiency. Importantly, as our studies were in progress, PiT-2 was identified as the causative gene for idiopathic basal ganglion calcification in people, and thus our studies noting compensatory mechanisms for phosphate transporters may help to explain how mutation of PiT-2 might lead to compensatory changes that actually facilitate vascular calcification. Clinically, our data provide a cautionary note on compensatory pathways that should be considered when attempting to translate inhibition of phosphate transport to clinical therapies. In addition to the Pi transport through PiTs, our preliminary findings also suggest a Pi transport- independent Pi sensing and signaling mechanism that mediates Pi-driving cell functions. PiT-1 and PiT-2 are high affinity, low capacity Pi transporters that form oligomers under low to normal extracellular Pi, leading to a influx of Pi as source for loading into matrix vesicles that mediate matrix calcification. Under high extracellular Pi, such as hyperphosphatemia in CKD, monomers form, resulting in exposure of cryptic site that binds to PiT adaptor proteins and thereby facilitates Erk1/2 phosphorylation and subsequent signaling to osteochondrogenic differentiation, autophagy, and apoptosis of VSMC. Therefore, in specific aim 1 of the proposed project we will improve scientific knowledge by delineating unique mechanisms responsible for vascular calcification in CKD-MBD and thereby uncover new therapeutic targets and drug targeting modalities that can treat vascular calcification and spare bone.
In specific aim 2, we will explore the novel concept of how Pi transport-independent Pi sensing and signaling process is controlled by differential oligomerization that induces VSMC osteochondrogenic phenotype change, apoptosis and autophagy. The proposed work will improve our understanding of how elevated Pi promotes vascular calcification and provide additional therapeutic targets for preventing or treating CKD-MBD.

Public Health Relevance

Vascular calcification, or hardening of the arteries, is a major problem in people with kidney disease. Our studies aim to understand the key factors that cause this problem. Understanding these processes will allow development of new drugs to treat the problem in the future.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL062329-14A1
Application #
8814070
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Srinivas, Pothur R
Project Start
1999-04-01
Project End
2018-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
14
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Washington
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wallingford, Mary Catherine; Chia, Jia Jun; Leaf, Elizabeth M et al. (2017) SLC20A2 Deficiency in Mice Leads to Elevated Phosphate Levels in Cerbrospinal Fluid and Glymphatic Pathway-Associated Arteriolar Calcification, and Recapitulates Human Idiopathic Basal Ganglia Calcification. Brain Pathol 27:64-76
Yamada, Shunsuke; Giachelli, Cecilia M (2017) Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone 100:87-93
Giachelli, Cecilia M; Speer, Mei Y (2017) Noncanonical Wnts at the Cusp of Fibrocalcific Signaling Processes in Human Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol 37:387-388
Paloian, Neil J; Leaf, Elizabeth M; Giachelli, Cecilia M (2016) Osteopontin protects against high phosphate-induced nephrocalcinosis and vascular calcification. Kidney Int 89:1027-1036
Wallingford, Mary C; Gammill, Hilary S; Giachelli, Cecilia M (2016) Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and laminin?1 expressing cells. Reprod Biol 16:13-26
Lin, Mu-En; Chen, Theodore; Leaf, Elizabeth M et al. (2015) Runx2 Expression in Smooth Muscle Cells Is Required for Arterial Medial Calcification in Mice. Am J Pathol 185:1958-69
Chavkin, Nicholas W; Chia, Jia Jun; Crouthamel, Matthew H et al. (2015) Phosphate uptake-independent signaling functions of the type III sodium-dependent phosphate transporter, PiT-1, in vascular smooth muscle cells. Exp Cell Res 333:39-48
Wallingford, Mary C; Giachelli, Cecilia M (2014) Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm. Mech Dev 133:189-202
Paloian, Neil J; Giachelli, Cecilia M (2014) A current understanding of vascular calcification in CKD. Am J Physiol Renal Physiol 307:F891-900
Wu, Meiting; Rementer, Cameron; Giachelli, Cecilia M (2013) Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int 93:365-73

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