Comparison of the effects of novel vitamin D receptor analog VS-105 and paricalcitol on chronic kidney disease-mineral bone disorder in an experimental model of chronic kidney disease.
When using vitamin D, the most important clinical problems are hypercalcemia, hyperphosphatemia, and vascular calcification. VS-105 is a novel vitamin D receptor (VDR) analog. In the present study, we compared the effects of VS-105 and paricalcitol on chronic kidney disease-mineral bone disorder (CKD-MBD) in a CKD rat model. We used male Sprague-Dawley (SD) rats and performed 5/6 nephrectomy at 8-9 weeks. At 10 weeks, the rats were classified into five groups and administered vehicle, low-dose paricalcitol (LP, 0.1μg/kg), high-dose paricalcitol (HP, 0.3μg/kg), low-dose VS-105 (LV, 0.2μg/kg), and high-dose VS-105 (HV, 0.6 μg/kg) three times a week for 10 weeks. There were no significant differences in blood pressure or renal function among the five groups. Alhough serum calcium levels were comparable between the LP and LV groups, they were higher in the HP group than in the HV group. Serum phosphate levels were higher in the paricalcitol-treated groups than in the VS-105-treated groups and paticularly higher in the HP group than in the other groups. The urinary excretion of phosphate was greater in the VS-105-treated groups than in the paricalcitol-treated groups. Serum parathyroid hormone (PTH) levels decreased and serum fibroblast growth factor-23 (FGF23) levels were elevated after administering paricalcitol and VS-105; however, serum FGF23 levels were remarkably elevated in the paricalcitol-treated groups. Further biochemical analyses revealed that the calcium content of the aorta was higher in the paricalcitol-treated groups than in the VS-105-treated group. VDR and Klotho expression in the kidney was significantly higher in the VS-105-treated groups than in the paricalcitol-treated groups although both agents increased these expressions. Our data suggest that VS-105 had a lesser effect on CKD-MBD than paricalcitol except in the case of serum PTH levels. The mechanism appears to be associated with the difference in VDR and Klotho expression.
Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: fhideki@med.kobe-u.ac.jp.
Hideki
H
Fujii
Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.
Yuriko
Y
Yonekura
Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.
Kentaro
K
Nakai
Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.
Keiji
K
Kono
Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.
Shunsuke
S
Goto
Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.
Shinichi
S
Nishi
D000818:Animals; D001011:Aorta / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015519:Bone Density; D001847:Bone Diseases / Q000378:metabolism*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry; D002118:Calcium / Q000097:blood; D004872:Ergocalciferols / Q000097:blood; D005346:Fibroblast Growth Factors / Q000097:blood; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D010758:Phosphorus / Q000097:blood / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000737:chemistry*; D014807:Vitamin D / Q000627:therapeutic use
C570781:5-(2-(1-(1-(3-hydroxy-2,3-dimethylbutoxy)ethyl)-7alpha-methyldihydro-1H-inden-4(2H,5H,6H,7H,7alphaH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol; D015415:Biomarkers; D004872:Ergocalciferols; C505605:Fgf23 protein, rat; D018167:Receptors, Calcitriol; D014807:Vitamin D; D010758:Phosphorus; D005346:Fibroblast Growth Factors; C084656:paricalcitol; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol; D002118:Calcium
CKD-MBD; FGF23; Klotho; VS-105; Vitamin D analog