Fate of the kidney vasculature during partial neonatal ureteral obstruction

新生儿输尿管部分梗阻期间肾脏脉管系统的命运

• 批准号: 10159245
• 负责人: MARIA LUISA Soledad SEQUEIRA-LOPEZ
• 金额: $ 36.34万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159245
• 关键词: Adult; Blood Vessels; Cell Compartmentation; Cell Fate Control; Cell Lineage; Cells; Child; Chronic; Chronic Kidney Failure; Clinical; Data; Development; Duct (organ) structure; Ductal Epithelial Cell; End stage renal failure; Endothelium; Enterobacteria phage P1 Cre recombinase; Excision; Family; Fetus; Fibrosis; Foundations; Genetic; Genetic Transcription; Goals; Growth; Human; Immunohistochemistry; Impairment; Infant; Injury; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Knowledge; Label; Lead; Maintenance; Modeling; Molecular; Morphogenesis; Morphology; Mus; Natural regeneration; Neonatal; Nephrons; Obstruction; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Phase; Play; Population; Procedures; Recombinants; Recovery; Regenerative Medicine; Regenerative capacity; Renal function; Renin; Reporter; Research Project Grants; Role; Second Pregnancy Trimester; Societies; Structure; Techniques; Testing; Therapeutic; Thinness; Tissues; Transgenic Mice; Trees; Tubular formation; Ureteral obstruction; Vascular Morphologic Change; Vascularization; Work; base; cell type; design; experimental study; in utero; inducible gene expression; injury and repair; interstitial; interstitial cell; kidney cell; kidney vascular structure; mouse model; mutant; neonatal mice; nephrogenesis; notch protein; novel strategies; novel therapeutics; organ growth; postnatal; prevent; progenitor; regeneration potential; regenerative; regenerative therapy; renal damage; repaired; response; urinary tract obstruction

ABSTRACT Obstructive nephropathy, the leading cause of chronic kidney disease in infants and children not only impairs nephrogenesis but can also lead to progressive destruction of immature and mature nephrons via injury to the vascular, tubular, and interstitial compartments. The proposed research project is designed to identify the vascular precursors and the mechanisms whereby they repair the injured kidney, using a model of reversible partial unilateral ureteral obstruction (pUUO) in the neonatal mouse, which parallels urinary tract obstruction in the human fetus. Our preliminary data using genetic cell fate tracing techniques show that during neonatal pUUO there are severe abnormalities in the renal arterial tree followed by loss of proximal tubular and collecting duct cells. Concomitant with the nephrovascular damage, there is expansion of interstitial cells ultimately leading to fibrosis. Remarkably, upon release of obstruction, reversal of the damage occurs with regeneration of the vasculature, proximal tubules and collecting ducts. The striking recovery observed after release of ureteral obstruction requires the reenactment of developmental pathways that control cell fate, positional information and organized growth. We propose that the kidney vasculature plays a direct and central role in the ability of the kidney to regenerate and repair after injury. Therefore, in this proposal we will test the interrelated hypotheses that ureteral obstruction leads to defective vascular morphogenesis and changes in cell fate and that that RBP-J (the transcriptional effector of all the Notch receptors) not only controls the normal development of the kidney vessels, but also the fate and regeneration of the vasculature and its associated nephrons after release of obstruction. In summary, we will explore how changes in cell identity and fate create massive morphological and functional changes which in turn determine whether the tissue will be healthy or unrecoverable. Specific Aim 1 will define the vascular changes of the postnatal kidney following obstructive nephropathy and after release, Specific Aim 2 will determine the fate of vascular cells using specific Cre recombinant and fluorescent reporter mouse lines, and Specific Aim 3 will determine whether Rbp-J plays a role in the regeneration and maintenance of the renal vasculature and associated nephrons during obstruction and after its release using mice with inducible expression of Cre recombinase and concomitant fluorescent reporter expression that allows to trace the fate of the mutant cells. The proposed work will fill an important gap in our knowledge: deciphering the cellular and molecular mechanisms involved in nephrovascular repair and regeneration has potential therapeutic implications for infants and children and the growing adult population suffering from chronic kidney disease.

抽象的 阻塞性肾病，婴儿和儿童的慢性肾脏疾病的主要原因不仅会损害 肾脏发生，但也可能导致通过损伤逐渐破坏未成熟和成熟的肾脏 血管，管状和间质室。拟议的研究项目旨在确定 血管前体和它们修复受伤肾脏的机制，使用可逆模型 新生小鼠中的部分单侧输尿管阻塞（PUUO），与尿路阻塞相似 人类胎儿。我们使用遗传细胞命运追踪技术的初步数据表明，在新生儿期间 puuo肾动脉树中存在严重异常，随后是近端管状和 收集管道细胞。与肾血管损伤伴随着，间质细胞的膨胀 最终导致纤维化。值得注意的是，释放阻塞后，损害的逆转随着 脉管系统的再生，近端小管和收集管道。在 释放输尿管障碍需要重新制定控制细胞命运的发育途径， 位置信息和有组织的增长。我们建议肾脏脉管系统直接发挥作用 肾脏在受伤后再生和修复的能力中的中心作用。因此，在这个建议中我们 将检验相互关联的假设，即输尿管阻塞会导致缺陷的血管形态发生和 细胞命运的变化以及RBP-J（所有Notch受体的转录效应器）不仅控制 肾脏血管的正常发育，以及脉管系统的命运和再生 释放障碍物后相关的肾单位。总而言之，我们将探讨细胞身份的变化和 命运产生了巨大的形态和功能变化，进而决定组织是否会 健康或无法恢复。特定的目标1将定义产后肾脏的血管变化。 阻塞性肾病和释放后，特定的目标2将使用血管细胞的命运 特定的CRE重组和荧光记者小鼠系，具体AIM 3将决定是否确定是否是否 RBP-J在肾脏脉管系统的再生和维持中起作用 在阻塞期间和使用小鼠释放后，具有CRE重组酶的诱导表达和 伴随荧光报告基因表达，允许追踪突变细胞的命运。提议 工作将填补我们的知识的重要空白：解读涉及的细胞和分子机制 肾血管修复和再生对婴儿和儿童具有潜在的治疗意义 患有慢性肾脏疾病的成年人口增长。

项目成果

Phylogeny and ontogeny of the renin-angiotensin system: Current view and perspectives.

• DOI: 10.1016/j.cbpa.2020.110879
• 发表时间: 2021-04
• 期刊: Comparative biochemistry and physiology. Part A, Molecular & integrative physiology
• 作者: Nishimura H;Sequeira-Lopez MLS
• 通讯作者: Sequeira-Lopez MLS

Stromal prorenin receptor is critical for normal kidney development.

基质肾素原受体对于正常肾脏发育至关重要。

• DOI: 10.1152/ajpregu.00320.2018
• 发表时间: 2019
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Yosypiv,IhorV;Sequeira-Lopez,MariaLuisaS;Song,Renfang;DeGoesMartini,Alexandre
• 通讯作者: DeGoesMartini,Alexandre

Ctcf is required for renin expression and maintenance of the structural integrity of the kidney.

• DOI: 10.1042/cs20200184
• 发表时间: 2020-07-17
• 期刊: Clinical science (London, England : 1979)
• 作者: Martinez MF;Martini AG;Sequeira-Lopez MLS;Gomez RA
• 通讯作者: Gomez RA

A primitive type of renin-expressing lymphocyte protects the organism against infections.

• DOI: 10.1038/s41598-021-86629-w
• 发表时间: 2021-03-31
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Belyea BC;Santiago AE;Vasconez WA;Nagalakshmi VK;Xu F;Mehalic TC;Sequeira-Lopez MLS;Gomez RA
• 通讯作者: Gomez RA

Patterns of differentiation of renin lineage cells during nephrogenesis.

肾发生过程中肾素谱系细胞的分化模式。

• DOI: 10.1152/ajprenal.00151.2021
• 发表时间: 2021
• 期刊: American journal of physiology. Renal physiology
• 作者: Kessel,Friederike;Steglich,Anne;Hickmann,Linda;LiraMartinez,Ricardo;Gerlach,Michael;Sequeira-Lopez,MariaLuisaS;Gomez,RAriel;Hugo,ChristianPM;Todorov,VladimirT
• 通讯作者: Todorov,VladimirT