title: Hypermethylation of the CaSR and VDR genes in the parathyroid glands in chronic kidney disease rats with high-phosphate diet.
abstract: Chronic kidney disease (CKD) disrupts mineral homeostasis and its representative pathosis is defined as secondary hyperparathyroidism (SHPT). SHPT occurs during the early course of progressive renal insufficiency, and is associated with mortality and cardiovascular events. SHPT results in reduction of calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) in the parathyroid glands during CKD. However, the precise mechanism of CaSR and VDR reduction is largely unknown. CKD was induced through two-step 5/6 nephrectomy, and then CKD rats and sham-operated rats were maintained for 8 weeks on diets containing 0.7 % phosphorus (normal phosphate) or 1.2 % phosphorus (high phosphate). In gene expression analysis, TaqMan probes were used for quantitative real-time polymerase chain reaction. Finally, CaSR and VDR protein expressions were analyzed using immunohistochemistry. DNA methylation analysis was performed using a restriction digestion and quantitative PCR. CaSR and VDR mRNA were reduced only in CKD rats fed the high-phosphorus diets (CKD HP), then CaSR and VDR immunohistochemical expressions were compatible with gene expression assay. SHPT was then confirmed only in CKD HP rats. Furthermore, sole CKD HP rats showed the hypermethylation in CaSR and VDR genes; however, the percentage methylation of both genes was low. Although CaSR and VDR hypermethylation was demonstrated in PTGs of CKD HP rats, the extent of hypermethylation was insufficient to support the relevance between hypermethylation and down-regulation of gene expression because of the low percentage of methylation. Consequently, our data suggest that mechanisms, other than DNA hypermethylation, were responsible for the reduction in mRNA and protein levels of CaSR and VDR in PTGs of CKD HP rats.
authors: Department of Anatomy, The Jikei University School of Medicine, Tokyo, Japan.|Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors: Taketo
authors: T
authors: Uchiyama
authors: Department of Anatomy, The Jikei University School of Medicine, Tokyo, Japan.
authors: Norifumi
authors: N
authors: Tatsumi
authors: Department of Anatomy, The Jikei University School of Medicine, Tokyo, Japan.|Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors: Sahoko
authors: S
authors: Kamejima
authors: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors: Tsuyoshi
authors: T
authors: Waku
authors: Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors: Ichiro
authors: I
authors: Ohkido
authors: Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors: Keitaro
authors: K
authors: Yokoyama
authors: Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors: Takashi
authors: T
authors: Yokoo
authors: Department of Anatomy, The Jikei University School of Medicine, Tokyo, Japan. maokabe@jikei.ac.jp.
authors: Masataka
authors: M
authors: Okabe
mesh_terms: D000818:Animals; D002908:Chronic Disease; D019175:DNA Methylation; D004195:Disease Models, Animal; D015870:Gene Expression; D006962:Hyperparathyroidism, Secondary / Q000209:etiology; D007674:Kidney Diseases / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008745:Methylation; D010280:Parathyroid Glands / Q000378:metabolism*; D016226:Phosphorus, Dietary / Q000008:administration & dosage*; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000378:metabolism*
chemical_list: D016226:Phosphorus, Dietary; D011506:Proteins; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing
keywords: Calcium-sensing receptor; Chronic kidney disease; DNA methylation; Epigenetics; Vitamin D receptor