Active vitamin D and its analogue, 22-oxacalcitriol, ameliorate puromycin aminonucleoside-induced nephrosis in rats
Active vitamin D and its analogue, 22-oxacalcitriol, ameliorate puromycin aminonucleoside-induced nephrosis in rats
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DOI：
10.1093/ndt/gfp117
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发表时间：
2009-08-01
影响因子：
6.1
通讯作者：
Isaka, Yoshitaka
中科院分区：
文献类型：
--
作者：
Matsui, Isao;Hamano, Takayuki;Isaka, Yoshitaka
背景最近的研究表明，足细胞损伤，导致蛋白尿，导致肾小管间质纤维化。虽然一些研究表明，维生素D的管理保护肾脏的结构和功能的系膜细胞增殖和/或过度的基质生产模型，维生素D对足细胞损伤的影响仍然不确定。在这项研究中，我们使用嘌呤霉素氨基糖苷肾病模型，研究了活性维生素D（骨化三醇）或其类似物22-氧骨化三醇（maxacalcitol）的给药是否可以预防足细胞损伤，该模型既没有系膜增殖，也没有基质积累。在蛋白尿发作前，肾1 α-羟化酶和24-羟化酶分别显著下调和上调，导致维生素D活化受损。此后，血清25-羟基维生素D随着尿中维生素D结合蛋白排泄量的增加而沿着下降。在证实足细胞表达维生素D受体和除RXR-α以外的所有类维生素A X受体（RXR）后，我们发现每日给予骨化三醇或其类似物22-氧代骨化三醇通过保护足细胞改善肾病状态，如结蛋白（足细胞损伤标记物）染色减少和nephrin和podocin上调所示。这些数据表明，维生素D系统的损害在足细胞损伤中蛋白尿的增加中起作用。我们证明了维生素D激活系统在足细胞损伤中的分解，并建立了维生素D在足细胞损伤中的预防作用。
Background. Recent studies have demonstrated that podocyte injury, which results in proteinuria, leads to tubulointerstitial fibrosis. Although some studies have revealed that vitamin D administration protects renal structure and function in mesangial cell proliferative and/or excessive matrix productive models, the effects of vitamin D on podocyte injury have remained uncertain.Methods. In this study, we examined whether administration of active vitamin D (calcitriol) or its analogue, 22-oxacalcitriol (maxacalcitol), is preventative in podocyte injury using the puromycin aminonucleoside nephrosis model with neither mesangial proliferation nor matrix accumulation.Results. Before the onset of proteinuria, renal 1 alpha-hydroxylase and 24-hydroxylase were markedly downregulated and up-regulated, respectively, leading to impaired vitamin D activation. Thereafter, serum 25-hydroxyvitamin D decreased along with the increased excretion of vitamin D-binding protein in urine. After confirming that podocytes express vitamin D receptor and all retinoid X receptors (RXRs) except RXR-alpha, we found that daily administration of calcitriol or its analogue 22-oxacalcitriol ameliorated the nephrotic state by protecting podocytes, as shown by the reduced staining of desmin (podocyte injury marker) and the upregulation of nephrin and podocin. These data suggest that the impairment of the vitamin D system plays a role in increasing proteinuria in podocyte injury.Conclusions. We demonstrated the breakdown of the vitamin D activation system in podocyte injury, and established a preventative role for vitamin D in podocyte injury.