Phosphate-Induced Renal Fibrosis Requires the Prolyl Isomerase Pin1.
Phosphate-Induced Renal Fibrosis Requires the Prolyl Isomerase Pin1.
复制标题
磷酸盐诱导的肾纤维化需要脯氨酰异构酶PIN1。
DOI：
10.1371/journal.pone.0150093
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Malter JS
中科院分区：
文献类型：
--
作者：
Shen ZJ;Hu J;Shiizaki K;Kuro-o M;Malter JS
肾小管间质纤维化是多种肾脏疾病常见的、破坏性的终点。在人类和啮齿动物中，纤维化与肾功能的丧失有很好的相关性。确定纤维化的调节因素可以提供新的治疗方法来减少疾病的进展或严重程度。在这里，我们表明，在一个具有良好特征的动物模型中，肽基-Pro异构酶Pin1是促进肾脏纤维化的重要分子贡献者。当饲喂高磷饲料(HPD)8-12周的野生型小鼠出现肾间质钙沉积、巨噬细胞浸润和细胞外基质(ECM)积聚时，Pin1基因缺失的小鼠表现出明显较少的病理改变。HPD可使WT和KO小鼠的血清PI显著升高，而KO小鼠的血钙较WT略有下降。此外，WT和KO HPD小鼠体重增加较少，但器官质量(肾、肺、脾、肝和心脏)正常。出乎意料的是，无论HPD如何，这两种基因型的患者最初的肾功能都没有受损。我们的结果表明，高PI饮食在对肾功能产生显着影响之前就会导致快速的肾脏纤维化，Pin1在纤维化过程中起着重要作用。
Tubulo-interstitial fibrosis is a common, destructive endpoint for a variety of kidney diseases. Fibrosis is well correlated with the loss of kidney function in both humans and rodents. The identification of modulators of fibrosis could provide novel therapeutic approaches to reducing disease progression or severity. Here, we show that the peptidyl-prolyl isomerase Pin1 is an important molecular contributor that facilitates renal fibrosis in a well-characterized animal model. While wild-type mice fed a high phosphate diet (HPD) for 8–12 weeks developed calcium deposition, macrophage infiltration and extracellular matrix (ECM) accumulation in the kidney interstitium, Pin1 null mice showed significantly less pathology. The serum Pi in both WT and KO mice were significantly increased by the HPD, but the serum Ca was slightly decreased in KO compared to WT. In addition, both WT and KO HPD mice had less weight gain but exhibited normal organ mass (kidney, lung, spleen, liver and heart). Unexpectedly, renal function was not initially impaired in either genotype irrespective of the HPD. Our results suggest that diet containing high Pi induces rapid renal fibrosis before a significant impact on renal function and that Pin1 plays an important role in the fibrotic process.