Does the adult kidney need its renin cells?

肾素生成细胞（RPC）位于成人肾脏的传入小动脉。它们是血浆肾素的来源，而血浆肾素是肾素-血管紧张素系统（RAS）的限速因子。最近，人们清楚地认识到，除了在RAS中的作用外，RPC对肾脏的功能和结构完整性也很重要。我们证实RPC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。肾素细胞祖生态位也以一种受调节的方式不断被新鲜细胞补充。此外，我们发现RPC通过产生促血管生成和促纤维化因子来保护肾脏微血管内皮。这些信号分子的产生在RPC中被精细地调节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表明，在基础条件下，成年小鼠肾RPC的消融不会导致任何主要的不良肾脏表型。这些发现也是出乎意料的，因为在RPC消融后RAS应该下调，从而导致灌注不足和循环障碍。因此，在拟议的项目中，我们的目标是在体内平衡受到挑战的情况下继续研究RPC在肾循环中的新功能。计划的实验将解决三个主要问题：首先，将研究RPC在肾素产生的生理调节中的作用。为此，我们将用不同的盐饮食治疗消融RPC小鼠或调节其血管紧张素II水平。观察到的肾脏血管功能的变化将与野生型对照动物进行比较。其次，研究慢性应激下切除RPC小鼠的肾脏表型。我们预计RPC对于应激信号的充分反应是必要的，因为它们以及RAS一般是生物体适应性反应的重要组成部分。第三，我们将探讨RPC在糖尿病肾脏中的作用。在这里，我们将比较两种不同糖尿病模型中野生型、rpc消融型和肾素缺乏型rpc特异性gs - α敲除小鼠的肾小球内皮的肾脏血管功能和结构。考虑到我们的研究结果，RPC对肾微内皮具有保护作用，我们认为RPC缺陷或减少的动物可能具有加重的表型。通过这个项目，我们希望阐明RPC在临床相关病理生理模型中的新功能。实验结果将有助于回答成人肾脏是否仅在特定条件下需要肾素细胞来维持其血管稳态的问题。

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.