Wnt/β-catenin信号调控肾素-血管紧张素系统(RAS)对AKI进展到CKD的功能与机制

Recent and robust clinical data support the association of episodes of acute kidney injury (AKI) with an increasing likelihood of developing chronic kidney disease (CKD). However, the exact pathologic mechanisms by which this occurs are still unknown. Our preliminary studies demonstrated that dysregulated activation of the key developmental signaling pathway Wnt/β-catenin in the pathogenesis of AKI. Interestingly, we recently identified renin angiotensin system (RAS) are downstream targets of Wnt/β-catenin signaling. As a result, the central hypothesis of this proposal is that Wnt/β-catenin signaling regulates RAS expression and mediates AKI to CKD progression. To test this, we design following studies in two specific aims. Aim 1 is to investigate the induction of local RAS in models of the progression from AKI to CKD and to elucidate the underlying mechanisms. Aim 2 is to investigate activation or blockade of Wnt/β-catenin signaling in regulating RAS expression and promoting AKI-CKD progression. These studies promise to offer important insights into understanding how AKI progresses to CKD. Undoubtedly, the data generated from this application will have wide implications in comprehending the pathogenesis of AKI-CKD progression, as well as in designing future therapeutic regimens for treatment.

急性肾损伤(AKI)是慢性肾脏病(CKD)进展的独立危险因素。然而AKI是如何引起CKD的发生发展的，其机制尚不明确。本课题组前期研究发现Wnt/β-catenin信号在急性肾损伤时被重新激活，且持续激活的Wnt信号促进AKI到CKD的进展；而且肾素-血管紧张素系统(RAS)的多个组分是Wnt信号的下游靶基因。因此，本课题提出“Wnt/β-catenin信号通过调控其下游靶基因RAS的表达从而促进AKI到CKD的进展”这一假说。为证实上述假说，本课题将从体内、体外两个层面研究Wnt信号的激活对RAS表达、肌成纤维细胞的活化及AKI进展到CKD的影响和调控机制。并用小分子抑制剂ICG-001靶向抑制β-catenin信号，干预AKI进展到CKD的可行性和有效性。本研究将有助于阐明AKI进展到CKD的致病机制，从而为临床防治AKI到CKD的发展开辟新的途径。

急性肾损伤(AKI)的发生率呈现不断增加趋势，而AKI不但致死率高，而且预后差，约7.5％的重症AKI患者需要长期透析，30%-70%将进展至慢性肾脏病 (CKD）甚至终末期肾病(ESRD)。因此，AKI 是CKD进展的独立危险因素。然而AKI是如何引起CKD的发生、发展的，其机制尚不明确。本课题组之前的研究发现续激活的Wnt/β-catenin信号促进了AKI到CKD的进展。但有其他研究发现，在AKI发生时Wnt/β-catenin信号的激活，有利于肾小管上皮细胞的修复。因此，如果提前给予Wnt/β-catenin信号的激动剂，则有可能预防AKI的发生，以及阻止AKI进展到CKD的肾脏纤维化。在本项目的资助下，本课题组研究发现，提前给予外源性Wnt1激动剂后，可以减少肾小管上皮细胞的凋亡，预防肾脏缺血再灌注引起的AKI发生。体外研究也证实Wnt1激动剂通过抑制肾小管上皮细胞相关凋亡蛋白的表达，减轻缺氧/复氧诱导的肾小管的损伤和凋亡。进一步利用小鼠构建了AKI-CKD的模型，并在术前通过尾静脉注射Wnt1质粒或腹腔注射β-catenin信号小分子抑制剂ICG-001。研究结果发现上调Wnt/β-catenin信号可减轻肾脏炎症反应、抑制促肾脏纤维化基因的表达，以及减少细胞外基质(ECM)的堆积，从而阻断AKI到CKD的进展。通过本研究，更加深入地揭示了Wnt/β-catenin信号在AKI阶段、AKI-CKD发生发展阶段起着不同的调控作用，初步阐明了AKI进展到CKD的分子机制，为临床防治AKI到CKD的发展开辟新的治疗靶点。