Regenerative and protective effects of renin cells on renal vasculature

肾素细胞对肾血管系统的再生和保护作用

• 批准号: 399229660
• 负责人: Professor Dr. Vladimir Todorov
• 金额: --
• 依托单位: Lehrstuhl für Physiologie und Pathophysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/399229660?language=en
• 关键词: Regenerative; protective; effects; renin; cells

Renin is produced by juxtaglomerular (JG) cells in the afferent arterioles of the kidney in adulthood. The JG cells are conventionally regarded as renin cells since they are the main source of renin which is the rate-limiting factor in plasma Renin-Angiotensin System (RAS). Recently, it becomes increasingly clear that independently of their role within RAS, the renin cells are important for the functional and structural integrity of the kidney. We already developed a novel inducible triple-transgenic mouse model to study the RAS-unrelated functions of the renin cells. We established that the renin cells serve as stem-cell-like precursor cells capable of differentiating to replace damaged intraglomerular cells after glomerular injury. The renin cell progenitor niche is also constantly refilled by fresh cells in a regulated fashion. Furthermore we deleted Gsα in JG cells. Upon binding of extracellular ligands to G protein-coupled receptors, Gsα catalyzes the intracellular production of the second messenger cAMP. We found that JG cell-specific Gsα deficiency leads to progressive kidney malfunction most prominently featured by renal microvascular endothelial injury with signs of thrombotic microangiopathy (TMA) and impaired production of VEGF in the renin cells.In the proposed project we aim to continue our studies by addressing two major issues:First, the significance of Gsα in renin cells in physiological and pathophysiological models with altered renal function will be studied. To this end, mice with induced Gsα deficiency in JG cells will be subjected to high-salt diet, RAS inhibition, severe arterial hypertension or acute renal TMA-like endothelial damage, and compared to wildtype control animals with regard to their kidney function. These experiments aim to further mechanistically explain the renal vascular phenotype of the renin cell-specific Gsα knockout mice as well as to identify new aspects of the protective and regenerative role of the renin cells. Second, the role of VEGF produced by the renin cells in the kidney will be investigated. Here, we will phenotype mice with induced deletion of VEGF in renin cells to prove if they will develop kidney damage similar the renin cell-specific Gsα-deficient mice. Furthermore, it will be studied whether renin cell-derived VEGF is protective in acute endothelial injury models.The proposed project is expected to provide further knowledge on the developing concept that the renin cells represent a unique cell niche necessary for both the physiological operation of the kidney and for its regeneration upon damage. It will also highlight the considerable regenerative potential of the mammalian kidney and support the idea that this potential could be mechanistically targeted by future therapeutic strategies.

在成年期，肾素由肾脏的传入小动脉中的肾小球（JG）细胞产生。由于JG细胞是血浆肾素-血管紧张素系统（RAS）中的限速因子，因此JG细胞通常被认为是肾素细胞，因为它们是肾素的主要来源。最近，越来越清楚的是，独立于它们在RAS中的作用，肾素细胞对于肾脏的功能和结构完整性是重要的。我们已经开发了一种新的诱导型三转基因小鼠模型来研究RAS无关的功能的肾素细胞。我们确定，肾素细胞作为干细胞样前体细胞，能够在肾小球损伤后分化以取代受损的肾小球内细胞。肾素细胞祖细胞龛也不断地被新鲜细胞以受调节的方式重新填充。此外，我们还删除了JG细胞中的Gsα。在细胞外配体与G蛋白偶联受体结合后，Gsα催化细胞内第二信使cAMP的产生。我们发现，JG细胞特异性Gsα缺乏导致进行性肾功能不全，最突出的特点是肾微血管内皮损伤的迹象血栓性微血管病（TMA）和血管内皮生长因子的生产受损的肾素cells.在拟议的项目中，我们的目标是继续我们的研究，解决两个主要问题：第一，Gsα在肾素细胞的生理和病理生理模型与肾功能改变的意义将进行研究。为此，将对JG细胞中诱导Gsα缺乏的小鼠进行高盐饮食、RAS抑制、重度动脉高血压或急性肾TMA样内皮损伤，并与野生型对照动物的肾功能进行比较。这些实验旨在进一步从机制上解释肾素细胞特异性Gsα基因敲除小鼠的肾血管表型，以及确定肾素细胞保护和再生作用的新方面。其次，将研究肾中由肾素细胞产生的VEGF的作用。在这里，我们将用诱导的肾素细胞中VEGF缺失的小鼠进行表型，以证明它们是否会发生类似于肾素细胞特异性Gsα缺陷小鼠的肾损伤。此外，它将研究是否是保护急性内皮损伤models.The拟议的项目，预计将提供进一步的知识，发展概念，即肾素细胞代表一个独特的细胞生态位所需的生理运作的肾脏和其再生后的损害。它还将突出哺乳动物肾脏的相当大的再生潜力，并支持这种潜力可以通过未来的治疗策略进行机械靶向的想法。