title: Phosphate binders prevent phosphate-induced cellular senescence of vascular smooth muscle cells and vascular calcification in a modified, adenine-based uremic rat model.
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.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: N
authors.initials: N
authors.lastname: Tatsumoto
authors.forename: M
authors.initials: M
authors.lastname: Tokumoto
authors.forename: H
authors.initials: H
authors.lastname: Noguchi
authors.forename: H
authors.initials: H
authors.lastname: Ooboshi
authors.forename: T
authors.initials: T
authors.lastname: Kitazono
authors.forename: K
authors.initials: K
authors.lastname: Tsuruya
mesh_terms: D000225:Adenine / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D002114:Calcinosis; D002119:Calcium Carbonate / Q000737:chemistry; D016922:Cellular Senescence / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000503:physiopathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000517:prevention & control; D007811:Lanthanum / Q000737:chemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects; D018384:Oxidative Stress; D010710:Phosphates / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000517:prevention & control; D015398:Signal Transduction; D014511:Uremia / Q000188:drug therapy / Q000378:metabolism*; D061205:Vascular Calcification / Q000378:metabolism*
chemical_list: D010710:Phosphates; C119467:lanthanum carbonate; D007811:Lanthanum; D002119:Calcium Carbonate; D000225:Adenine