title: Cardiac effect of vitamin D receptor modulators in uremic rats.
abstract: Vitamin D receptor (VDR) modulators (VDRMs) are commonly used to control secondary hyperparathyroidism (SHPT) associated with chronic kidney disease, and are associated with beneficial outcomes in cardiovascular disease. In this study, we compared the cardiac effect of VS-105, a novel VDRM, with that of paricalcitol in 5/6 nephrectomized uremic rats. Male Sprague-Dawley rats were 5/6 nephrectomized, fed a standard diet for 4 weeks to establish uremia, and then treated (intraperitoneally, 3 times/week) with vehicle (propylene glycol), paricalcitol (0.025 and 0.15μg/kg), or VS-105 (0.05 and 0.3μg/kg) for 4 weeks. In uremic rats, neither VDRM (low and high doses) altered serum creatinine and phosphorus levels. Serum calcium was significantly higher with high dose paricalcitol compared to sham rats. PTH levels were significantly decreased with low dose paricalcitol and VS-105, and were further reduced in the high dose groups. Interestingly, serum FGF23 was significantly higher with high dose paricalcitol compared to sham rats, whereas VS-105 had no significant effect on FGF23 levels. Left ventricle (LV) weight and LV mass index determined by echocardiography were significantly suppressed in both high dose VDRM groups. This suppression was more evident with VS-105. Western blotting showed significant decreases in a fibrosis marker TGF-β1 in both high dose VDRM groups (vs. vehicle) and Masson trichrome staining showed significant decreases in cardiac fibrosis in these groups. These results suggest that VS-105 is less hypercalcemic than paricalcitol and has favorable effects on SHPT and cardiac parameters that are similar to those of paricalcitol in uremic rats. The cardioprotective effect is a noteworthy characteristic of VS-105.
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan. Electronic address: mizobu@med.showa-u.ac.jp.
authors.forename: Masahide
authors.initials: M
authors.lastname: Mizobuchi
authors.affiliation: Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ogata
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Yamazaki-Nakazawa
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Hosaka
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Kondo
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Koiwa
authors.affiliation: Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Kinugasa
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Shibata
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D004452:Echocardiography; D004872:Ergocalciferols / Q000494:pharmacology; D005346:Fibroblast Growth Factors; D015870:Gene Expression; D006352:Heart Ventricles / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D009392:Nephrectomy; D010281:Parathyroid Hormone; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1; D014511:Uremia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: 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; D002316:Cardiotonic Agents; D004872:Ergocalciferols; C505605:Fgf23 protein, rat; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D053773:Transforming Growth Factor beta1; D005346:Fibroblast Growth Factors; C084656:paricalcitol; D003404:Creatinine; D002117:Calcitriol; D002118:Calcium
keywords: Cardiac remodeling; Fibrosis; Vitamin D receptor; Vitamin D receptor modulator