Does the adult kidney need its renin cells?

成人肾脏需要肾素细胞吗？

• 批准号: 470138795
• 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
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/470138795?language=en
• 关键词: Does; adult; kidney; need; its

The renin-producing cells (RPC) are located in the afferent arterioles of the kidney in adulthood. They are the source of plasma renin which is the rate-limiting factor in Renin-Angiotensin-System (RAS). Recently, it became clear that independently of their role within RAS, the RPC are important for the functional and structural integrity of the kidney. We established that the RPC 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 manner. Furthermore, we found that the RPC protect the renal microvascular endothelium by producing pro-angiogenic and pro-fibrotic factors. It appears that the production of these signaling molecules in the RPC is finely tuned to maintain the normal function of the renal capillaries. However, our latest experiments surprisingly demonstrated that ablation of the renal RPC in adult mice does not lead to any major adverse kidney phenotype at basal conditions. These findings were unexpected also because upon RPC ablation the RAS should be downregulated thus resulting in hypoperfusion and circulatory disorders.Therefore in the proposed project, we aim to continue our studies on the novel functions of the RPC in the renal circulation at conditions where homeostasis is challenged.The planned experiments will address three major issues:First, the role of RPC during the physiological regulation of renin production will be studied. To this end, we will treat mice with ablated RPC with different salt diets or will modulate their angiotensin II levels. The observed changes in renal vascular function will be compared to those in wildtype control animals. Second, the kidney phenotype of mice with ablated RPC subjected to chronic stress will be investigated. We expect that the RPC would be necessary for an adequate response to stress signals because they as well as RAS in general are essential parts of the adaptive reactions of the organism.Third, we will explore the role of the RPC in the diabetic kidney. Here we will compare the renal vascular function and structure with a focus on glomerular endothelium of wildtype, RPC-ablated, and renin-deficient RPC-specific Gs-alpha knockout mice in two different models of Diabetes mellitus. Considering our findings that the RPC are protective of the renal microendothelium we suggest that animals with defective or diminished RPC may have an aggravated phenotype.With this project, we expect to shed light on the novel functions of RPC in clinically relevant pathophysiological models. The results from the proposed experiments should help to answer the question of whether the adult kidney needs its renin cells only under certain conditions to maintain its vascular homeostasis.

成人肾脏的输入小动脉中有大量的肾素生成细胞（RPC）。它们是血浆肾素的来源，血浆肾素是肾素-血管紧张素系统（RAS）的限速因子。最近，人们越来越清楚，独立于其在RAS中的作用，RPC对肾脏的功能和结构完整性很重要。我们确定RPC作为干细胞样的前体细胞，能够在肾小球损伤后分化取代受损的肾小球内细胞。肾素细胞祖细胞龛也以受调节的方式不断被新鲜细胞重新填充。此外，我们发现RPC通过产生促血管生成因子和促纤维化因子来保护肾微血管内皮。看来，这些信号分子在RPC中的生产是微调，以维持肾毛细血管的正常功能。然而，我们最新的实验令人惊讶地证明，成年小鼠肾RPC的消融在基础条件下不会导致任何主要的不利肾脏表型。这些发现也是出乎意料的，因为RPC消融后，RAS应该下调，从而导致低灌注和循环障碍。因此，在拟议的项目中，我们的目标是继续我们的研究在肾循环中的RPC的新功能，在条件下的稳态受到挑战。计划的实验将解决三个主要问题：首先，RPC的作用在生理调节肾素生产将被研究。为此，我们将用不同的盐饮食治疗具有消融RPC的小鼠，或者将调节它们的血管紧张素II水平。将观察到的肾血管功能变化与野生型对照动物中的变化进行比较。其次，将研究慢性应激下消融RPC小鼠的肾脏表型。我们预计，RPC将是必要的充分响应的压力信号，因为他们以及RAS一般的有机体的适应性反应的重要组成部分。第三，我们将探讨RPC在糖尿病肾脏的作用。在这里，我们将比较两种不同糖尿病模型中野生型、RPC消融和肾素缺陷型RPC特异性Gs-α基因敲除小鼠的肾血管功能和结构，重点关注肾小球内皮。考虑到我们的研究结果，RPC是保护肾微内皮细胞，我们认为，动物与缺陷或减少RPC可能有加重phenotype.With这个项目，我们希望阐明的新功能RPC在临床相关的病理生理模型。从拟议的实验结果应该有助于回答这个问题，成人肾脏是否需要它的肾素细胞只在某些条件下，以维持其血管内稳态。