The Role of Renin-lineage Cells from the Juxtaglomerular Apparatus for Mesangial cell Regeneration after glomerular Injury

肾小球旁装​​置肾素谱系细胞在肾小球损伤后系膜细胞再生中的作用

• 批准号: 310297900
• 负责人: Professor Dr. Christian Hugo
• 金额: --
• 依托单位: Bereich Nephrologie/Dialyse
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/310297900?language=en
• 关键词: Role; Renin; lineage; Cells; Juxtaglomerular

In previous studies creating and using a triple transgenic mouse line, we have shown a novel regenerative mechanism, where renin-positive juxtaglomerular adult progenitor cells were recruited from the juxtaglomerular apparatus into glomeruli after severe mesangial cell injury. Hereby, upon entering the glomerulus these recruited cells lose their renin-positivity and differentiate into mesangial cells (de novo acquiring mesangial cell markers).In this grant proposal, the role / importance of this mechanism of precursor cell recruitment for mesangial cell regeneration after severe injury will be explored.To analyze the role of renin expression for precursor cell function, we created mice with a specific renin knockout in renin-positive adult progenitor cells via crossing our triple-transgenic mice (mRen-rtTAm2/LC-1/tdTomato) with mice carrying a floxed renin gene (mRen-rtTAm2/LC-1/tdTomato/Ren flox). To characterize the overall importance of renin-positive adult progenitor cells for glomerular repair, we will ablate these cells by cell type specific inducible expression of either diphtheria toxin A (mRen-rtTAm2/LC-1/tdTomato/DTA) or diphtheria toxin receptor (mRen-rtTAm2/LC-1/tdTomato/R-DTR) and subsequent stimulation. Furthermore, we will study mRen-rtTAm2/LC-1/Confetti mice to identify the clonality pattern (i.e. random, focal-segmental, centripetal) of renin-derived precursor cells during mesangial repopulation.The isolation, phenotypic characterization, and transcriptom analysis of renin-positive progenitor cells compared to normal mesangial cells, will further help us to better understand the potential and unique features of these cells. In perspective, the anticipated results from the present proposal will demonstrate the special features and potential of the renin-positive precursor cells and allow us to therapeutically use/manipulate them for an improvement of this regenerative mechanism in the future.

在以前的研究中，创建和使用一个三重转基因小鼠系，我们已经显示了一种新的再生机制，其中肾素阳性肾小球成体祖细胞从肾小球器官招募到肾小球后，严重的系膜细胞损伤。因此，在进入肾小球后，这些募集的细胞失去其肾素阳性并分化为系膜细胞（从头获得肾小球系膜细胞标记物）。在本资助提案中，将探讨严重损伤后这种前体细胞募集机制对肾小球系膜细胞再生的作用/重要性。为了分析肾素表达对前体细胞功能的作用，我们通过将我们的三重转基因小鼠（mRen-rtTAm 2/LC-1/tdTomato）与携带floxed凝乳酶基因的小鼠（mRen-rtTAm 2/LC-1/tdTomato/Ren flox）杂交，在凝乳酶阳性成体祖细胞中产生了特异性凝乳酶敲除的小鼠。为了表征肾素阳性成体祖细胞对于肾小球修复的总体重要性，我们将通过白喉毒素A（mRen-rtTAm 2/LC-1/tdTomato/DTA）或白喉毒素受体（mRen-rtTAm 2/LC-1/tdTomato/R-DTR）的细胞类型特异性诱导表达和随后的刺激来消融这些细胞。此外，我们将研究mRen-rtTAm 2/LC-1/Confetti小鼠，以确定在系膜再生过程中肾素衍生的前体细胞的克隆性模式（即随机，局灶节段，向心）。与正常系膜细胞相比，肾素阳性祖细胞的分离，表型特征和转录组分析，将进一步帮助我们更好地了解这些细胞的潜力和独特的功能。从长远来看，本提案的预期结果将证明肾素阳性前体细胞的特殊功能和潜力，并允许我们在未来治疗性地使用/操纵它们以改善这种再生机制。