Pathophysiological significance of the cell cycle in acute kidney injury

细胞周期在急性肾损伤中的病理生理意义

• 批准号: 499521306
• 负责人: Professor Dr. Roland Schmitt
• 金额: --
• 依托单位: Klinik für Nieren- und Hochdruckerkrankungen
• 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/499521306?language=en
• 关键词: Pathophysiological; significance; cell; cycle; acute

Acute kidney injury is a serious clinical condition in which kidney function declines abruptly and for which there is no specific therapy. In many cases, kidney function can recover, but permanent damage also occurs, leading to end stage renal disease. Whether kidney recovery is successful depends on several factors. One important component is tubular cell proliferation, which is usually considered to contribute to the repair of damaged renal tubules. However, in our preliminary work, we observed that damage-induced proliferation can be not only reparative but also detrimental. In transgenic mice specifically lacking the cell cycle protein cyclin D1 in the proximal tubule, we observed that reduced proliferative capacity protects the kidney. These findings fit with previous observations from other groups with pharmacological cell cycle inhibition. In the present application, we will investigate the underlying processes of this phenomenon and we will test whether the principle of cyclin D1 antagonization can be exploited therapeutically. To address the latter point, we will use an siRNA-based knockdown strategy in a mouse model that could allow for potential clinical translation. To address the question of the mechanistic basis, we performed transcriptome analyses in preliminary work in which we examined differences in proximal tubules with and without cyclin D1 ablation. In doing so, we were looking for an association of cyclin D1 with damage-aggravating transcripts. Indeed, we found transcriptional differences exclusively for cell cycle genes, so we assume that the protective mechanism arises directly from inhibition of cell cycle activation per se. As a crucial factor, we now want to test the 'cellular energy hypothesis', in which we postulate that cell cycle blockade is nephroprotective by protecting against excessive energy expenditure of cell cycle activation. We plan to test this hypothesis in cell culture experiments as well as in mouse and zebrafish embryos by using different damage models and proliferation interventions to analyze cell and tissue responses in response to cell cycle activation. To this end we will use energy carrier measurements, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry imaging (MALDI-TOF-MSI), and cellular damage analysis. Together, the expected results should help to better understand the role of tubular cell proliferation in acute renal failure. The long-term goal is to establish a basis that will allow the derivation of new therapeutic strategies.

急性肾损伤是一种严重的临床病症，其中肾功能突然下降并且没有特定的治疗方法。在许多情况下，肾功能可以恢复，但也会发生永久性损伤，导致终末期肾病。肾脏恢复是否成功取决于几个因素。一个重要组成部分是肾小管细胞增殖，通常认为这有助于修复受损的肾小管。然而，在我们的初步工作中，我们观察到损伤引起的增殖不仅可以是修复性的，而且是有害的。在近曲小管中特别缺乏细胞周期蛋白细胞周期蛋白 D1 的转基因小鼠中，我们观察到增殖能力的降低可以保护肾脏。这些发现与其他具有药理细胞周期抑制作用的小组之前的观察结果相符。在本申请中，我们将研究这种现象的潜在过程，并测试细胞周期蛋白D1拮抗作用的原理是否可以用于治疗。为了解决后一点，我们将在小鼠模型中使用基于 siRNA 的敲低策略，该策略可以实现潜在的临床转化。为了解决机制基础的问题，我们在前期工作中进行了转录组分析，其中我们检查了有和没有细胞周期蛋白 D1 消融的近端小管的差异。在此过程中，我们寻找细胞周期蛋白 D1 与损伤加重转录本的关联。事实上，我们发现了专门针对细胞周期基因的转录差异，因此我们假设保护机制直接来自细胞周期激活本身的抑制。作为一个关键因素，我们现在想要测试“细胞能量假说”，其中我们假设细胞周期阻断通过防止细胞周期激活的过度能量消耗而具有肾保护作用。我们计划通过使用不同的损伤模型和增殖干预来分析细胞和组织对细胞周期激活的反应，在细胞培养实验以及小鼠和斑马鱼胚胎中测试这一假设。为此，我们将使用能量载体测量、基质辅助激光解吸/电离飞行时间质谱成像 (MALDI-TOF-MSI) 和细胞损伤分析。总之，预期结果应有助于更好地了解肾小管细胞增殖在急性肾衰竭中的作用。长期目标是建立一个基础，以便推导出新的治疗策略。