Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl/kl mice.
Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl/kl mice.
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DOI：
10.1038/srep06563
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发表时间：
2014-10-09
影响因子：
4.6
通讯作者：
Muragaki Y
中科院分区：
文献类型：
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作者：
Sun Y;Zhou G;Gui T;Shimokado A;Nakanishi M;Oikawa K;Sato F;Muragaki Y
先前的研究表明Klotho对单侧输尿管梗阻（UUO）诱导的肾小管间质纤维化（RTF）提供肾脏保护。由于现有的研究主要使用杂合Klotho突变（HT）小鼠进行，我们专注于UUO对纯合Klotho突变（kl/kl）小鼠的影响。来自HT小鼠的UUO肾脏显示出比野生型（WT）小鼠显著更高水平的RTF和TGF-β/Smad 3信号传导，而这两者在kl/kl小鼠中均受到极大抑制。与来自HT小鼠的细胞相比，从kl/kl小鼠分离的原代近端肾小管上皮细胞培养物细胞在TGF-β1诱导的上皮间质转化（EMT）中未显示抑制。在肾上皮细胞系NRK 52 E中，向培养基中加入大量无机磷酸盐（Pi）、FGF 23或骨化三醇以模拟kl/kl小鼠的体内稳态。Pi和FGF 23均不拮抗TGF-β1诱导的EMT。与此相反，骨化三醇以剂量依赖性方式改善TGF-β1诱导的EMT。维生素D3缺乏饮食使kl/kl小鼠中的血清1，25（OH）2维生素D3水平正常化，并增强UUO诱导的RTF和TGF-β/Smad 3信号传导。总之，kl/kl小鼠中UUO诱导的RTF的减轻是由于血清1，25（OH）2维生素D3升高引起的TGF-β1信号转导抑制。
Previous studies have suggested that Klotho provides reno-protection against unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis (RTF). Because the existing studies are mainly performed using heterozygous Klotho mutant (HT) mice, we focused on the effect of UUO on homozygous Klotho mutant (kl/kl) mice. UUO kidneys from HT mice showed a significantly higher level of RTF and TGF-β/Smad3 signaling than wild-type (WT) mice, whereas both were greatly suppressed in kl/kl mice. Primary proximal tubular epithelial culture cells isolated from kl/kl mice showed no suppression in TGF-β1-induced epithelial mesenchymal transition (EMT) compared to those from HT mice. In the renal epithelial cell line NRK52E, a large amount of inorganic phosphate (Pi), FGF23, or calcitriol was added to the medium to mimic the in vivo homeostasis of kl/kl mice. Neither Pi nor FGF23 antagonized TGF-β1-induced EMT. In contrast, calcitriol ameliorated TGF-β1-induced EMT in a dose dependent manner. A vitamin D3-deficient diet normalized the serum 1,25 (OH)2 vitamin D3 level in kl/kl mice and enhanced UUO-induced RTF and TGF-β/Smad3 signaling. In conclusion, the alleviation of UUO-induced RTF in kl/kl mice was due to the TGF-β1 signaling suppression caused by an elevated serum 1, 25(OH)2 vitamin D3.