Mizobuchi Masahide, Ogata Hiroaki, Yamazaki-Nakazawa Ai, Hosaka Nozomu, Kondo Fumiko, Koiwa Fumihiko, Kinugasa Eriko, Shibata Takanori
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama, Japan.
J Steroid Biochem Mol Biol. 2016 Oct;163:20-7. doi: 10.1016/j.jsbmb.2016.03.028. Epub 2016 Apr 9.
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.
维生素D受体（VDR）调节剂（VDRM）常用于控制与慢性肾脏病相关的继发性甲状旁腺功能亢进（SHPT），并对心血管疾病具有有益作用。在本研究中，我们比较了新型VDRM VS-105与帕立骨化醇对5/6肾切除的尿毒症大鼠的心脏影响。雄性Sprague-Dawley大鼠接受5/6肾切除，喂食标准饮食4周以建立尿毒症，然后用赋形剂（丙二醇）、帕立骨化醇（0.025和0.15μg/kg）或VS-105（0.05和0.3μg/kg）腹腔注射（每周3次）治疗4周。在尿毒症大鼠中，两种VDRM（低剂量和高剂量）均未改变血清肌酐和磷水平。与假手术大鼠相比，高剂量帕立骨化醇使血清钙显著升高。低剂量帕立骨化醇和VS-105使甲状旁腺激素（PTH）水平显著降低，高剂量组进一步降低。有趣的是，与假手术大鼠相比，高剂量帕立骨化醇使血清成纤维细胞生长因子23（FGF23）显著升高，而VS-105对FGF23水平无显著影响。通过超声心动图测定的左心室（LV）重量和LV质量指数在两个高剂量VDRM组中均显著降低。VS-105的这种抑制作用更明显。蛋白质印迹法显示，两个高剂量VDRM组（与赋形剂相比）的纤维化标志物转化生长因子-β1显著降低，Masson三色染色显示这些组的心脏纤维化显著减少。这些结果表明，在尿毒症大鼠中，VS-105的高钙血症作用低于帕立骨化醇，并且对SHPT和心脏参数具有与帕立骨化醇相似的有利作用。心脏保护作用是VS-105的一个值得注意的特征。
