Zebrafish model of acute kidney injury

摘要 急性肾损伤是一个常见的医学问题，具有重大的社会影响。它导致了 死亡风险增加，住院时间延长，住院费用增加。肾脏有一种 非凡的再生能力，但尽管有这种再生的潜力， 需要透析的AKI患者仍有50%-80%。因此，仍然有必要发展医疗 增强肾脏组织再生的内在能力的方法。利用这些 肾脏再生的内在机制将有助于设计最佳的治疗策略 AKI患者。为了制定这样的战略，关键是要通过以下方式了解这些机制 哪个肾脏能从损伤中恢复。最近的研究表明，上皮修复，尽管受到 间质、血管和循环因子是肾上皮固有的过程。因此， 确定固有的上皮修复的基本机制是关键 了解肾脏如何从急性肾损伤中恢复。长期以来，人们一直认为细胞的增殖， 细胞去分化和细胞迁移可能在上皮修复中起重要作用。 不幸的是，AKI的传统哺乳动物模型不允许足够的时空控制 研究这些过程在肾脏修复中所起的确切作用。因此，我们开发了一部小说 斑马鱼模型的AKI，克服了哺乳动物系统的限制。使用这个模型，我们 发现集体细胞迁移是存活的上皮细胞对急性损伤的早期反应 比细胞增殖反应早至少几个小时。这是一项新的发现， 集体细胞迁移是肾脏修复的中心。此外，我们发现在肾脏期间 发育集体上皮迁移刺激继发于细胞拉伸的上皮增殖 由这种集体迁徙引起的。在肾脏修复过程中也存在相同的成分-细胞 迁移，随后的细胞伸展，以及细胞增殖的延迟开始。建议进行的研究 涉及一系列实验，将调查这种生物力学联系是否是主要的 再生肾上皮细胞增殖反应的决定因素。我们还将测试 PI3K信号转导细胞的增殖反应。此外，我们还将调查 通过结合我们的损伤模型和化学处理的方法研究肾脏修复过程中的上皮可塑性 再生的斑马鱼。总体而言，这些研究将促进我们对 迁移、增殖、去分化和化生的基本细胞过程适用于 急性损伤后的肾脏修复。他们将为设计有针对性的疗法奠定基础 肾脏修复的各个组成部分。

Summary Acute kidney injury is a common medical problem with a significant impact on society. It results in the increased risk of death, lengthening of hospital stay and increased cost of hospitalization. Kidney has a remarkable capacity to regenerate but despite this potential for regeneration, the mortality rate for the AKI patients who require dialysis is still 50%-80%. Thus, there remains a need to develop medical approaches that would enhance the intrinsic ability of the kidney tissue to regenerate. Utilizing these intrinsic mechanisms of kidney regeneration will help to design optimal strategies for the treatment of patients with AKI. In order to develop such strategies, it is critical to understand the mechanisms by which kidney recovers from injury. It has been recently shown that epithelial repair, albeit influenced by stromal, vascular and circulating factors, is a process intrinsic to the kidney epithelium. Therefore, identifying the basic mechanisms governing the intrinsic epithelial restitution is central to the understanding of how kidney recovers from AKI. It has been long acknowledged that cell proliferation, cell de-differentiation and perhaps cell migration may play a significant role in epithelial restitution. Unfortunately, traditional mammalian models of AKI do not allow for a sufficient spatio-temporal control to investigate the precise role these processes play in kidney repair. Thus, we developed a novel zebrafish model of AKI that overcomes the limitations of mammalian systems. Using this model, we discovered that collective cell migration is an early response of surviving epithelium to acute injury that precedes the cell proliferative response by at least several hours. This is a novel finding that places collective cell migration at the center of kidney repair. Furthermore, we found that during kidney development collective epithelial migration stimulates epithelial proliferation secondary to cell stretch induced by this collective migration. The same components are present during kidney repair - cell migration, subsequent cell stretch, and a delayed onset of cell proliferation. The proposed study involves a series of experiments that will investigate whether this biomechanical link is a primary determinant of cell proliferative response in regenerating kidney epithelia. We will also test the role of Pi3K signaling in mediating the proliferative response. In addition, we will investigate the degree of epithelial plasticity during kidney repair by combining our injury model with a chemical treatment of the regenerating zebrafish. Overall, these studies will advance our understanding of the interplay between basic cellular processes of migration, proliferation, de-differentiation and metaplasia as they apply to kidney repair after acute injury. They will set the stage for designing targeted therapies addressing various components of kidney repair.