Tubular regeneration and renal cell carcinoma following kidney transplantation - pathomechanisms

与正常人群相比，肾移植术后恶性肿瘤的发生率增加了2-4倍，5年后恶性肿瘤的死亡率约为16%。除了钙调神经磷酸酶抑制剂为基础的免疫抑制的促癌作用外，移植过程中不可避免的缺血再灌注损伤所导致的免疫机制也发挥了作用。这种移植引起的急性肾功能衰竭通常是可逆的，尽管肾小管的实际再生能力尚不清楚，祖细胞的增殖和分化小管细胞的肥大在多大程度上只是对组织和功能急性丧失的动态反应。此外，急性组织损伤通过干细胞群的大量增殖和/或分化细胞的多倍体基因组改变导致DNA改变和修复。这些都是肿瘤发生的潜在机制。在小鼠模型中，与最初的假设相反，最近证明了Pax2+祖细胞在小管再生中的关键作用。由于缺血再灌注损伤，在大约50%的病例中也观察到恶性肿瘤。这些细胞对肾移植后再生和恶性肿瘤发展的实际影响将在小鼠肾移植模型中进行研究。本课题旨在结合小鼠肾移植经验和急性药物性肾损伤小管再生的研究，建立肿瘤肾移植模型。该模型将用于研究Pax2+小管上皮细胞在小管再生和肿瘤发生中的作用。特别是转基因小鼠(pax2 . rta; TetO.Cre;R26. rta；五彩纸屑)可以用来研究这个问题。Pax2+祖细胞的克隆谱系追踪可以在这些动物中进行。此外，我们还将研究同种异体移植在持续免疫抑制下对Pax2+祖细胞的免疫学影响。最后，我们将探讨不同促增殖物质的潜在肾保护作用。对于这里介绍的项目，已经存在上巴伐利亚政府批准的动物实验申请。基于本项目的研究结果，我们期望探索新的方法来减少缺血再灌注引起的肾损伤，从而稳定肾移植后的肾功能，并由此提高移植后的长期存活率。此外，我们期望能够开发出预防移植肾中肾细胞癌发展的方法。

The incidence of malignancy after renal transplantation is increased 2-4-fold compared with the normal population, and deaths from malignancy occur in approximately 16% of cases after 5 years. In addition to the pro-carcinogenic effect of calcineurin inhibitor-based immunosuppression, immunological mechanisms due to the ischemia-reperfusion injury inevitable during transplantation also play a role. This transplantation-induced acute renal failure is usually reversible, although the actual regenerative capacity of renal tubules is unclear and to what extent proliferation of progenitor cells and hypertrophy of differentiated tubule cells merely represent a dynamic response to the acute loss of tissue and function. Furthermore, acute tissue injury leads to DNA alteration and repair through extensive proliferation of stem cell populations and/or polyploid genome alterations of differentiated cells. All also potential mechanisms for tumorigenesis. In a mouse model, contrary to initial assumptions, a crucial role of Pax2+ progenitor cells in tubule regeneration has recently been demonstrated. As a consequence of ischemia-reperfusion damage, malignancy was also observed in approximately 50% of cases. The actual influence of these cells on regeneration and on the other hand malignancy development after kidney transplantation will now be investigated in this work in a murine kidney transplantation model. The aim of this project is to establish a tumor-in-kidney transplantation model based on our experience with murine kidney transplantation and studies on tubule regeneration in acute drug-induced kidney injury. This model will be used to investigate the role of Pax2+ tubular epithelial cells on tubule regeneration and tumorigenesis. Specially genetically modified mice (Pax2.rtTA; TetO.Cre;R26.Confetti) are available to study this issue. Clonal lineage tracing of Pax2+ progenitor cells can be performed in these animals. In addition, the immunological influence on Pax2+ progenitor cells by allogeneic transplantation under continuous immunosuppression will also be investigated. Finally, potential nephro-protective effects of different pro-proliferative substances will be investigated. For the project presented here, an animal experiment application approved by the government of Upper Bavaria already exists. Based on the findings of this project, we expect to investigate new approaches to minimize ischemia-reperfusion-induced renal injury and thus stabilize renal function after kidney transplantation as well as a resulting improvement in long-term graft survival. Furthermore, we expect to be able to develop approaches to prevent the development of renal cell carcinomas in the kidney grafts.