Senolysis in kidney disease: Therapeutic potential and risks

在过去的十年中，细胞衰老（细胞命运程序）对衰老以及几种疾病过程的重要性已经被证明。衰老细胞被锁定在非分裂状态，其中它们不再能够维持组织完整性，并且通过产生促炎微环境而对正常器官维持有害。事实上，靶向衰老细胞的新策略已经在几个器官系统中显示出对抗功能衰退、慢性炎症和年龄依赖性修复能力丧失的希望。衰老细胞随着年龄的增长而在肾脏中积累，并且作为肾脏疾病的一部分独立于年龄发生，使其成为治疗方法的重要靶点。我们的目的是在我们建立的细胞和动物模型中评估已知的衰老药物的有效性和安全性。我们将测试的假设，选择性杀死衰老细胞可以用来改善年龄相关的肾功能丧失，并抵消加速老化表型。为此，我们将在目标1中评估减少肾脏中衰老细胞负担的最有效方法。基于最有前途的衰老清除化合物的体外选择，我们将进一步评估这些药物的短期应用是否会改善按时间顺序老化的小鼠以及经历了促衰老肾应激的年轻小鼠的急性肾损伤后的结果。此外，我们将启动长期药物应用，以研究其对肾脏时间老化变化的影响。目的2解决的问题，是否围手术期应用这种senolytic化合物会导致移植结果的改善时，边缘供体肾被利用。对于这种方法，我们将首先在体外测试不同的衰老清除药物在灌注条件下消除衰老细胞的潜力，然后进一步评估预处理器官在同基因和同种异体环境中的结果。在一个转化的方法，我们将使用移植的肾脏，看看我们的研究结果是否可以转化为人类setting.The总体目标是双重的：首先，评估“senolysis”作为一种新的方法，改善疾病的天然肾脏和肾移植的结果;其次，提供证据衰老细胞的存在和肾功能下降之间的因果关系。

The importance of cellular senescence, a cell fate program, for aging, but also several disease processes has been shown over the past decade. Senescent cells are locked in a non-dividing state, in which they are no longer able to maintain tissue integrity and are harmful for normal organ maintenance by creation of a pro-inflammatory microenvironment. In fact, novel strategies in targeting senescent cells have shown promise in several organ systems to counteract functional decline, chronic inflammation and age-dependent loss of repair capacity. Senescent cells accumulate in the kidney with advancing age and also occur independent of age as a part of renal diseases making them an important target for therapeutic approaches.Our objective is to evaluate known senolytic drugs for their efficacy and safety in our established cellular and animal models. We will test the hypothesis that selective killing of senescent cells can be utilized to improve age-associated loss of kidney function and to counteract the accelerated aging phenotype. For this purpose we will evaluate in Aim 1 the most effective way to decrease the burden of senescent cells in the kidney. Based on in vitro selection of the most promising senolytic compounds, we will then further evaluate whether short-term application of those drugs will improve outcome after acute kidney injury in chronologically aged mice as well as in young mice, which have undergone pro-senescent kidney stress. In addition, we will initiate long-term drug application to study its effect on chronological aging changes in the kidney. Aim 2 addresses the question whether peri-operative application of such senolytic compounds leads to an improvement in transplantation outcome when marginal donor kidneys are utilized. For this approach, we will first test different senolytic drugs ex vivo for their potential to eliminate senescent cells under perfusion conditions and will then further evaluate the outcome of pre-treated organs in isogeneic and allogeneic settings. In a translational approach, we are going to use explanted kidneys to see whether our findings can be translated into the human setting.The overall goal of this study is twofold: firstly, to evaluate ‘senolysis’ as a novel approach for improving the outcome of diseased native kidneys and of renal transplants; and secondly, to provide evidence for the causal relationship between the presence of senescent cells and renal functional decline.