Maintenance of vascular integrity by pericytes is essential for normal kidney function
Maintenance of vascular integrity by pericytes is essential for normal kidney function
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DOI：
10.1152/ajprenal.00030.2016
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发表时间：
2016-12-01
影响因子：
4.2
通讯作者：
Duffield, Jeremy S.
中科院分区：
文献类型：
--
作者：
Lemos, Dario R.;Marsh, Graham;Duffield, Jeremy S.
周细胞是组织驻留的间充质祖细胞，在解剖学上与脉管系统相关，已显示其参与组织再生。在这里，我们测试了这样一个假设，即肾周细胞，来源于胚胎发育过程中的FoxD1（+）中胚层祖细胞，是出生后肾脏稳态所必需的。将白喉毒素递送至FoxD1Cre：：RsDTR转基因小鼠导致>90%的肾周细胞的选择性消融，而不是其他细胞谱系。96小时内血浆肌酐、血尿素氮和白蛋白尿的突然增加表明周细胞消融小鼠的急性肾损伤。周细胞的丧失导致肾小管上皮细胞中中性脂质空泡的快速积聚、线粒体肿胀和凋亡。周细胞消融导致内皮细胞肿胀，血管稳态标志物表达减少，以及管周毛细血管损失。尽管观察到损伤，但未观察到急性炎症反应的迹象。在体内肾周细胞中表达的基因的途径富集分析鉴定了基底膜蛋白、血管生成因子和调节血管张力的因子作为血管功能的主要调节因子。使用新的微生理装置，我们概括了人肾管周毛细血管包被周细胞，并表明周细胞调节渗透性，基底膜沉积，和微血管张力。这些发现表明，通过微血管系统的积极支持，周细胞是必不可少的成人肾脏稳态。
Pericytes are tissue-resident mesenchymal progenitor cells anatomically associated with the vasculature that have been shown to participate in tissue regeneration. Here, we tested the hypothesis that kidney pericytes, derived from FoxD1(+) mesodermal progenitors during embryogenesis, are necessary for postnatal kidney homeostasis. Diphtheria toxin delivery to FoxD1Cre::RsDTR transgenic mice resulted in selective ablation of >90% of kidney pericytes but not other cell lineages. Abrupt increases in plasma creatinine, blood urea nitrogen, and albuminuria within 96 h indicated acute kidney injury in pericyte-ablated mice. Loss of pericytes led to a rapid accumulation of neutral lipid vacuoles, swollen mitochondria, and apoptosis in tubular epithelial cells. Pericyte ablation led to endothelial cell swelling, reduced expression of vascular homeostasis markers, and peritubular capillary loss. Despite the observed injury, no signs of the acute inflammatory response were observed. Pathway enrichment analysis of genes expressed in kidney pericytes in vivo identified basement membrane proteins, angiogenic factors, and factors regulating vascular tone as major regulators of vascular function. Using novel microphysiological devices, we recapitulated human kidney peritubular capillaries coated with pericytes and showed that pericytes regulate permeability, basement membrane deposition, and microvascular tone. These findings suggest that through the active support of the microvasculature, pericytes are essential to adult kidney homeostasis.