Hippo信号通路靶向lincRNA-p21抑制肾小管上皮细胞自噬促进糖尿病肾病的机制研究

肾小管损伤促进DKD进展，自噬活性的维持对肾小管上皮细胞功能的发挥至关重要，但是肾小管上皮细胞自噬活性降低在肾小管损伤和DKD进展中的作用和机制尚不完全清楚。我们前期研究发现，DKD小鼠肾小管上皮细胞自噬活性下降伴随Hippo信号通路核心蛋白YAP以及lincRNA-p21的异常升高，而体外抑制肾小管上皮细胞内YAP或lincRNA-p21的活性或表达均有助于缓解高糖对自噬活性的抑制。此外，抑制YAP的活性也可下调lincRNA-p21在肾小管上皮细胞内的表达。因此，我们提出假设：Hippo信号通路的核心蛋白YAP活化之后可靶向上调lincRNA-p21抑制肾小管上皮细胞自噬活性并推动DKD进展。为验证该假说，本项目拟通过细胞、分子和动物模型三个层次的研究阐明Hippo信号通路靶向lincRNA-p21调控肾小管上皮细胞自噬在DKD进程中的作用和机理，为寻找DKD新型治疗靶点提供理论依据。

Tubular injury plays a critical role in the pathogenesis of diabetic kidney disease (DKD), while autophagy homeostasis is essential to the maintenance of structure and function in tubular epithelial cells. Nevertheless, the roles and mechanisms of autophagy dysfunction in tubular epithelial cells during the development of DKD still remains largely unknown. Our preliminary iv vivo findings demonstrate that autophagy was suppressed in tubular epithelial cells of type 2 diabetic mice (db/db mice), which was accompanied by remarkably increased expression of YAP (Yes-associated protein 1, YAP1; also known as YAP) and lincRNA-p21 (Long intergenic non-coding RNA p21). Moreover, our previous in vitro findings tell that inhibition of YAP or knockdown of lincRNA-p21 could protect tubular epithelial cells from high glucose-elicited autophagy dysfunction. Notably, inhibition of YAP resulted in the downregulation of lincRNA-p21 in tubular epithelial cells. Accordingly, we propose that activated YAP, the essential transcriptional co-activator in the downstream of Hippo signaling pathway, can promote lincRNA-p21 expression through enhancing transcriptional activity of multiple transcriptional factors such as TEADs (TEA domain family members). Increased lincRNA-p21 subsequently leads to autophagy dysfunction in tubular epithelial cells by suppressing the transcription of autophagy-related molecules and sequestering autophagy-related proteins, hence contributing to tubular injury and pathological lesions in the progression of DKD. In order to test our research hypothesis, we will take advantage of comprehensive and diversified experimental plans and techniques to clarify the roles and mechanisms of Hippo signaling pathway-mediated lincRNA-p21 in the development of DKD by triggering tubular autophagy perturbation, aimed to yield theoretical evidence for exploring novel therapeutic targets for DKD.