转录因子FoxM1调控Wnt/b-catenin与Hippo通路的串话在AKI向CKD转化中的机制研究

临床上近1/3的急性肾损伤（AKI）并未得到完全恢复而向慢性肾病（CKD）发生转化。肾小管是AKI时肾损伤的关键部位，残存小管上皮细胞去分化、增殖是AKI后肾损伤修复的关键环节，Wnt/b-catenin通路是引发小管细胞去分化，促进小管修复的关键通路。然而，预实验显示Wnt/b-catenin通路在急性期后持续激活，并通过重编程因子KLF4与Hippo通路串话，维持去分化小管上皮细胞的分泌表型，通过促进TGF-b和CTGF合成和分泌，促使AKI向CKD转化；而转录因子FoxM1可能是上游调控Wnt/b-catenin激活的关键因子。基于AKI向CKD转化是由于AKI后肾脏修复并未得到适时终止，持续修复导致CKD发生的观点，本课题拟在AKI-CKD模型中，以FoxM1和KLF4为切入点，于急性期后适时终止肾脏的修复过程，探索阻止AKI向CKD转化的靶点与策略。

Nearly 1/3 of acute kidney injury (AKI) did not fully recover clinically. The transition of AKI to chronic kidney disease (CKD) has become an important factor in the pathogenesis of CKD. Renal tubules are the key points of renal injury in AKI. After AKI, the dedifferentiation and proliferation of renal tubular epithelial cells are the key step to promote renal repairmen after AKI, while the Wnt/-catenin pathway is the key pathway to induce the dedifferentiation of tubular epithelium. However, in preliminary study we observed that the Wnt/b-catenin pathway continues to activate after the acute phase of AKI. The transcription factor FoxM1 may be a key upstream factor in regulating the activation of Wnt/b-catenin pathway. The Wnt/b-catenin pathway promotes the expression and activation of YAP, the central active molecule in the Hippo pathway, through the reprogramming factor KLF4, and maintains the secretory phenotype of dedifferentiated tubular epithelial cells, and continually synthesizes and secrets TGF- and CTGF. Based on the concept that the transition of AKI to CKD is the consequence that AKI-CKD transition is the kidney repairmen after AKI does not terminated duly, continually repair lead to scar formation CKD, we plan to test the hypothesis in AKI-CKD animal model with FoxM1 and KLF4 as the breakthrough point via timely termination of kidney repair process after the acute phase to prevent the transition of AKI-CKD. The implementation of the project will be helpful to explore the molecular mechanism of transition of AKI-CKD, as well explore potential targets and strategies for clinical prevent AKI-CKD transition.