E2F-1对MRPL12的转录调控在糖尿病肾小管上皮细胞衰老中的作用

肾小管上皮细胞衰老是影响糖尿病肾病（DKD）的重要机制，其中线粒体生物合成能力降低是其关键环节，但具体机制尚未完全阐明。线粒体核糖体蛋白12（MRPL12）作为第一个鉴定为哺乳动物特征的线粒体核糖体蛋白，涉及到多种细胞过程，如细胞增殖、凋亡和核糖体之外的细胞周期调控。研究发现体外培养人肾小管上皮细胞，能量过度供应（高糖培养）通过MRPL12影响线粒体呼吸和能量代谢。针对本项目，通过生物信息学技术预测，参与线粒体合成的E2F-1可能是调控MRPL12的转录因子。据此本项目提出科学假说：高糖环境下，肾脏MRPL12广泛下降参与肾小管上皮细胞衰老进而影响DKD发生发展；E2F-1对MRPL12的转录调控是DKD肾小管上皮细胞MRPL12表达减少的上游机制。本项目拟采用体内、体外实验相结合的方法对上述科学问题进行论证。完成本项目，对于深入理解细胞衰老调控以及DKD的病生理机制均具有重要意义。

Senescence of renal tubular epithelial cells (TECs) is the key pathogenic event of diabetic kidney disease (DKD) with impaired mitochondrial biogenesis as one hallmark. However, the concrete mechanisms underlying diabetes-induced TECs senescence are not fully elucidated. Mitochondrial ribosomal protein 12 (MRPL12) is the first mitochondrial ribosomal protein identified as characteristic of mammals and is involved in a variety of cellular processes, cell proliferation, apoptosis and cell cycle. Previous study has reported that decreased expression of MRPL12 was associated with reduced mitochondrial OXPHOS in proximal tubular epithelial cells (PTECs) and overexpression of MRPL12 could alleviated the impairment of OXPHOS induced by long term high glucose. We use bioinformatics analysis to predict that E2F-1, an important factor involved in mitochondrial biogenesis, may be a transcription factor regulating MRPL12. Thereby, we hypothesized that regulate the expression of MRPL12 affects the senescence of renal tubular epithelial cells, accordingly modulate the occurrence and development of DKD;the regulation of MRPL12 by transcription factor E2F-1 is the upstream mechanism of DKD mitochondrial biosynthesis. Herein, we will employ both in-vivo and in-vitro experiments to demonstrate this hypothesis. This study will be of significance in deepening current understanding of cell senescence, and the pathogenesis of DKD as well.