Phosphate Binders Prevent Phosphate-Induced Cellular Senescence of Vascular Smooth Muscle Cells and Vascular Calcification in a Modified, Adenine-Based Uremic Rat Model

S. Yamada, N. Tatsumoto, M. Tokumoto, H. Noguchi, H. Ooboshi, T. Kitazono, K. Tsuruya

Research output: Contribution to journalArticle

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Abstract

Clinical and experimental studies have reported that phosphate overload plays a central role in the pathogenesis of vascular calcification in chronic kidney disease. However, it remains undetermined whether phosphate induces cellular senescence during vascular calcification. We established a modified uremic rat model induced by a diet containing 0.3 % adenine that showed more slowly progressive kidney failure, more robust vascular calcification, and longer survival than the conventional model (0.75 % adenine). To determine the effect of phosphate on senescence of vascular smooth muscle cells (VSMCs) and the protective effect of phosphate binders, rats were divided into four groups: (1) normal control rats; (2) rats fed with the modified adenine-based diet (CKD); (3) CKD rats treated with 6 % lanthanum carbonate (CKD-LaC); and (4) CKD rats treated with 6 % calcium carbonate (CKD-CaC). After 8 weeks, CKD rats showed circumferential arterial medial calcification, which was inhibited in CKD-LaC and CKD-CaC rats. CKD rats showed increased protein expression of senescence-associated β-galactosidase, bone-related proteins, p16 and p21, and increased oxidative stress levels in the calcified area, which were inhibited by both phosphate binders. However, serum levels of oxidative stress and inflammatory markers, serum fibroblast growth factor 23, and aortic calcium content in CKD-CaC rats were higher than those in CKD-LaC rats. In conclusion, phosphate induces cellular senescence of VSMCs in the modified uremic rat model, and phosphate binders can prevent both cellular senescence and calcification of VSMCs via phosphate unloading. Our modified adenine-based uremic rat model is useful for evaluating uremia-related complications, including vascular calcification.

Original languageEnglish
Pages (from-to)347-358
Number of pages12
JournalCalcified Tissue International
Volume96
Issue number4
DOIs
Publication statusPublished - Mar 13 2015

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Vascular Calcification
Cell Aging
Adenine
Vascular Smooth Muscle
Smooth Muscle Myocytes
Phosphates
Oxidative Stress
Galactosidases
Diet
Calcium Carbonate
Uremia
Chronic Renal Insufficiency
Renal Insufficiency

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine
  • Endocrinology

Cite this

Phosphate Binders Prevent Phosphate-Induced Cellular Senescence of Vascular Smooth Muscle Cells and Vascular Calcification in a Modified, Adenine-Based Uremic Rat Model. / Yamada, S.; Tatsumoto, N.; Tokumoto, M.; Noguchi, H.; Ooboshi, H.; Kitazono, T.; Tsuruya, K.

In: Calcified Tissue International, Vol. 96, No. 4, 13.03.2015, p. 347-358.

Research output: Contribution to journalArticle

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abstract = "Clinical and experimental studies have reported that phosphate overload plays a central role in the pathogenesis of vascular calcification in chronic kidney disease. However, it remains undetermined whether phosphate induces cellular senescence during vascular calcification. We established a modified uremic rat model induced by a diet containing 0.3 {\%} adenine that showed more slowly progressive kidney failure, more robust vascular calcification, and longer survival than the conventional model (0.75 {\%} adenine). To determine the effect of phosphate on senescence of vascular smooth muscle cells (VSMCs) and the protective effect of phosphate binders, rats were divided into four groups: (1) normal control rats; (2) rats fed with the modified adenine-based diet (CKD); (3) CKD rats treated with 6 {\%} lanthanum carbonate (CKD-LaC); and (4) CKD rats treated with 6 {\%} calcium carbonate (CKD-CaC). After 8 weeks, CKD rats showed circumferential arterial medial calcification, which was inhibited in CKD-LaC and CKD-CaC rats. CKD rats showed increased protein expression of senescence-associated β-galactosidase, bone-related proteins, p16 and p21, and increased oxidative stress levels in the calcified area, which were inhibited by both phosphate binders. However, serum levels of oxidative stress and inflammatory markers, serum fibroblast growth factor 23, and aortic calcium content in CKD-CaC rats were higher than those in CKD-LaC rats. In conclusion, phosphate induces cellular senescence of VSMCs in the modified uremic rat model, and phosphate binders can prevent both cellular senescence and calcification of VSMCs via phosphate unloading. Our modified adenine-based uremic rat model is useful for evaluating uremia-related complications, including vascular calcification.",
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