Regenerative and protective effects of renin cells on renal vasculature

肾素是由成年肾脏传入小动脉中的肾小球旁细胞产生的。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，而肾素是血浆肾素-血管紧张素系统（RAS）的限速因子。最近，越来越清楚的是，除了在RAS中的作用外，肾素细胞对肾脏的功能和结构完整性也很重要。我们已经建立了一种新的可诱导的三重转基因小鼠模型来研究肾素细胞与ras无关的功能。我们证实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取代受损的肾小球内细胞。肾素细胞祖位也以一种受调节的方式不断被新鲜细胞补充。此外，我们在JG细胞中删除了Gsα。在细胞外配体与G蛋白偶联受体结合后，gsa α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障碍，最显著的特征是肾微血管内皮损伤，伴有血栓性微血管病变（TMA）的迹象和肾素细胞中VEGF的产生受损。在这个项目中，我们的目标是通过解决两个主要问题来继续我们的研究：第一，将研究肾素细胞中Gsα在肾功能改变的生理和病理生理模型中的意义。为此，JG细胞中诱导Gsα缺乏的小鼠将遭受高盐饮食、RAS抑制、严重动脉高血压或急性肾tma样内皮损伤，并与野生型对照动物进行肾功能比较。这些实验旨在进一步从机制上解释肾素细胞特异性Gsα敲除小鼠的肾血管表型，并发现肾素细胞保护和再生作用的新方面。其次，研究肾素细胞产生的VEGF在肾脏中的作用。在这里，我们将对肾素细胞中VEGF诱导缺失的小鼠进行表型分析，以证明它们是否会出现与肾素细胞特异性gs α-缺陷小鼠相似的肾损伤。此外，我们还将研究肾素细胞来源的VEGF在急性内皮损伤模型中是否具有保护作用。拟议的项目预计将进一步了解肾素细胞代表肾脏生理运作和损伤再生所必需的独特细胞生态位的发展概念。它还将突出哺乳动物肾脏的巨大再生潜力，并支持这种潜力可能成为未来治疗策略的机械目标的想法。

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.