Angiopoietin-1 deficiency increases renal capillary rarefaction and tubulointerstitial fibrosis in mice.
Angiopoietin-1 deficiency increases renal capillary rarefaction and tubulointerstitial fibrosis in mice.
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DOI：
10.1371/journal.pone.0189433
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Jeansson M
中科院分区：
文献类型：
--
作者：
Loganathan K;Salem Said E;Winterrowd E;Orebrand M;He L;Vanlandewijck M;Betsholtz C;Quaggin SE;Jeansson M
肾小管间质纤维化的存在预示着肾功能的进行性下降，与其根本原因无关。肾微血管损伤是纤维化进展的主要因素，并且需要鉴定在纤维化中调节内皮的因子，因为它们可能是治疗肾脏疾病的候选靶标。目前的研究调查血管生成素-1（Angpt 1），内皮酪氨酸激酶受体Tek（也称为Tie 2）的配体的损失如何影响肾小管间质纤维化和肾脏微血管。诱导型Angpt 1敲除小鼠进行单侧输尿管梗阻（UUO）以诱导纤维化，并在梗阻后长达10天的不同时间点收集肾脏。aSMA染色显示，在UUO后3、6和10天，Angpt 1缺陷型肾脏与野生型小鼠相比具有显著更多的纤维化。UUO后3天的进一步研究显示Angpt 1缺陷小鼠中Col 1a 1和波形蛋白显著增加，以及Tgfb 1，Col 1a 1，Fn 1和CD 44的基因表达增加。肾损伤分子1（Kim 1/Havcr 1）在Angpt 1缺陷小鼠中在UUO后1天和3天显著增加，表明Angpt 1缺陷小鼠在纤维化过程的早期损伤更严重。内粘蛋白染色显示，UUO后3天毛细血管稀疏明显，与野生型小鼠的UUO肾脏相比，Angpt 1缺陷型小鼠在UUO后6天和10天毛细血管显著减少。RNA测序显示UUO后3天内皮细胞的几种标志物下调，Angpt 1缺陷小鼠的Emcn、Plvap、Pecam 1、Erg和Tek进一步下调。我们的研究结果表明，血管生成素1的损失是中央在毛细血管稀疏和纤维化，并提出操纵，以维持血管生成素1水平可能会减缓纤维化的进展。
Presence of tubulointerstitial fibrosis is predictive of progressive decline in kidney function, independent of its underlying cause. Injury to the renal microvasculature is a major factor in the progression of fibrosis and identification of factors that regulate endothelium in fibrosis is desirable as they might be candidate targets for treatment of kidney diseases. The current study investigates how loss of Angipoietin-1 (Angpt1), a ligand for endothelial tyrosine-kinase receptor Tek (also called Tie2), affects tubulointerstitial fibrosis and renal microvasculature. Inducible Angpt1 knockout mice were subjected to unilateral ureteral obstruction (UUO) to induce fibrosis, and kidneys were collected at different time points up to 10 days after obstruction. Staining for aSMA showed that Angpt1 deficient kidneys had significantly more fibrosis compared to wildtype mice 3, 6, and 10 days after UUO. Further investigation 3 days after UUO showed a significant increase of Col1a1 and vimentin in Angpt1 deficient mice, as well as increased gene expression of Tgfb1, Col1a1, Fn1, and CD44. Kidney injury molecule 1 (Kim1/Havcr1) was significantly more increased in Angpt1 deficient mice 1 and 3 days after UUO, suggesting a more severe injury early in the fibrotic process in Angpt1 deficient mice. Staining for endomucin showed that capillary rarefaction was evident 3 days after UUO and Angpt1 deficient mice had significantly less capillaries 6 and 10 days after UUO compared to UUO kidneys in wildtype mice. RNA sequencing revealed downregulation of several markers for endothelial cells 3 days after UUO, and that Angpt1 deficient mice had a further downregulation of Emcn, Plvap, Pecam1, Erg, and Tek. Our results suggest that loss of Angpt1 is central in capillary rarefaction and fibrogenesis and propose that manipulations to maintain Angpt1 levels may slow down fibrosis progression.
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影响因子：
3.3
作者：
Kramann, Rafael;Humphreys, Benjamin D.
通讯作者：
Humphreys, Benjamin D.
影响因子：
12.3
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影响因子：
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作者：
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Betsholtz C
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作者：
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影响因子：
13.6
作者：
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通讯作者：
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