足细胞线粒体（Podocyte mitochondria, Pmt）损伤及功能障碍在糖尿病肾病（DN）发生、进展中起重要作用，但高糖环境下Pmt损伤的病理特征与调控机制仍不明确。我们前期研究发现高糖环境下Pmt分裂异常，长管状线粒体减少、小球状线粒体增多，并伴随AKAP1/Drp1表达和磷酸化改变。本项目拟研究AKAP1在DN进展中Pmt分裂异常与功能障碍的作用及机制。通过建立糖尿病动物模型、高糖培养足细胞及DN病人肾活检标本，比较正常和疾病状态下Pmt结构形态与功能改变特点、评价Pmt代谢异常在足细胞损伤中的作用；通过稳定转染AKAP1及其磷酸化结构域缺失突变质粒和应用特异性足细胞AKAP1基因敲除小鼠，评价改变AKAP1表达及活性对Pmt分裂与功能障碍以及足细胞存活状态的影响。本项目旨在揭示糖尿病状态下Pmt损伤的病理与代谢改变特征及调节信号，为寻求DN新的治疗靶点提供理论和实验依据。

Podocyte mitochondrial injury and dysfunction have been regarded as a key factor in the development and progression of diabetic nephropathy (DN). But the pathological characteristics and the mechanism of podocyte mitochondrial injury caused by high glucose exposure are still unclear. Our previous studies demonstrated that high glucose exposure resulted in mitochondrial fragmentation, and alteration of AKAP1/Drp1 expression and phosphorylation. The objective of this project is to investigate the role and the potential mechanism of AKAP1 in podocyte mitochondrial fission and dysfunction in DN. A diabetic model, cultured podocytes stimulated by high glucose and biopsy specimens from DN patients will be used to evaluate the high glucose effects on podocyte injury and characteristics of mitochondrial structure and function. AKAP1 expression and activity will be altered via building podocyte-specific AKAP1 knockout mice and AKAP1 construct transfection; then, we will explore the role of AKAP1 in mitochondrial fission and podocyte injury during high glucose exposure. This investigation will unravel the characteristics of the mitochondrial structure and function in the progression of DN and its regulatory mechanism, through which new therapeutic targets may be identified.