Dietary phosphate restriction suppresses phosphaturia but does not prevent FGF23 elevation in a mouse model of chronic kidney disease.
Dietary phosphate restriction suppresses phosphaturia but does not prevent FGF23 elevation in a mouse model of chronic kidney disease.
复制标题
在慢性肾病小鼠模型中，膳食磷酸盐限制可抑制磷酸盐尿，但不能防止 FGF23 升高。
DOI：
10.1038/ki.2013.194
复制
发表时间：
2013
影响因子：
19.6
通讯作者：
Stubbs,JasonR
中科院分区：
文献类型：
--
作者：
Zhang,Shiqin;Gillihan,Ryan;He,Nan;Fields,Timothy;Liu,Shiguang;Green,Troy;Stubbs,JasonR
成纤维细胞生长因子23（FGF 23）是一种磷酸尿激素，在终末期肾病中血清中显著增加;然而，导致这种增加的机制尚不清楚。在此，我们使用Col 4 α3基因敲除小鼠（一种表现出CKD的Alport病小鼠模型）检测慢性肾病（CKD）中磷酸盐潴留是否与血清中FGF 23升高有关。我们发现，在进行性氮质血症的8周龄和12周龄CKD小鼠中，血清FGF 23显著升高，沿着磷排泄分数增加。中度和重度磷酸盐限制减少了8周的磷排泄分数，但血清FGF 23水平仍然显着升高。到12周时，中度磷酸盐限制进一步增加FGF 23水平，而重度磷酸盐限制导致严重的骨矿化缺陷和骨中FGF 23产生减少。对照饮食的CKD小鼠血清1，25-二羟维生素D（1，25（OH）2D）水平较低，renalCyp 24 α 1基因表达是野生型小鼠的3倍。严重的磷酸盐限制增加了CKD小鼠8周时的1，25（OH）2D水平，并降低了renalCyp 24 α 1基因表达，尽管血清FGF 23持续升高。在对照饮食的CKD小鼠中Renalklothogene表达下降，但在严格限制磷酸盐的情况下有所改善。因此，饮食磷酸盐限制降低了CKD小鼠中磷的排泄分数，而与血清FGF 23水平无关。
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that in end-stage renal disease is markedly increased in serum; however, the mechanisms responsible for this increase are unclear. Here, we tested whether phosphate retention in chronic kidney disease (CKD) is responsible for the elevation of FGF23 in serum using Col4α3 knockout mice, a murine model of Alport disease exhibiting CKD. We found a significant elevation in serum FGF23 in progressively azotemic 8- and 12-week-old CKD mice along with an increased fractional excretion of phosphorus. Both moderate and severe phosphate restriction reduced fractional excretion of phosphorus by 8 weeks, yet serum FGF23 levels remained strikingly elevated. By 12 weeks, FGF23 levels were further increased with moderate phosphate restriction, while severe phosphate restriction led to severe bone mineralization defects and decreased FGF23 production in bone. CKD mice on a control diet had low serum 1,25-dihydroxyvitamin D (1,25(OH)2D) levels and 3-fold higher renalCyp24α1gene expression compared to wild-type mice. Severe phosphate restriction increased 1,25(OH)2D levels in CKD mice by 8 weeks and lowered renalCyp24α1gene expression despite persistently elevated serum FGF23. Renalklothogene expression declined in CKD mice on a control diet, but improved with severe phosphate restriction. Thus, dietary phosphate restriction reduces the fractional excretion of phosphorus independent of serum FGF23 levels in mice with CKD.