锌转运体8对糖尿病肾病肾小管上皮细胞转分化的影响及机制研究

Diabetic nephropathy (DN) is an important microvascular complication in diabetes patients and the prevalence has progressively increased in recent years. DN is also the leading cause of chronic kidney failure and end stage renal disease and the patients may require dialysis or kidney transplantation. Evidence has demonstrated that Zn deficiency may induce the fibrosis in lung, liver etc. Although Zn deficiency is found to be associated with the development of diabetes and DN, the effects of Zn deficiency on tubulointerstitial fibrosis in DN and its underlying mechanism is still not clarified. Recent genetic studies have demonstrated that the common variants in the gene encoded for Zinc transpoter 8 (ZnT8) confer higher risk susceptibility to diabetes. We have recently found that ZnT8 is highly expressed in both human and rat renal tubular epithelial cells. Therefore, we have a hypothesis that ZnT8 dysfunction and Zinc deficiency may play an important role in the development of DN. In this study, we shall investigate the functional characteristics of ZnT8 in kidneys of ZnT8 knockout mice and cultured kidney tubular epithelial cells. The purposes of this study are to explore the role and underlying mechanism of ZnT8 dysfunction and Zinc deficiency in tubulointerstitial fibrosis and the development of DN, and to provide new information for clinical care and targeted therapy in DN.

糖尿病肾病是糖尿病严重的并发症之一。肾小管病变及肾间质纤维化是糖尿病肾病病理过程中的一个重要环节，而糖尿病和糖尿病肾病患者均存在不同程度的锌缺乏。研究资料业已表明锌缺乏与肺和肝等纤维化密切相关，但对锌缺乏在糖尿病肾病肾间质纤维化所产生的病理作用尚不清楚。近年来研究发现一种锌转运体(ZnT8) 基因DNA多态性以及抗体的功能下降与糖尿病密切相关。我们在前期研究工作中，发现ZnT8在人和大鼠肾小管上皮细胞中表达，很可能它的结构和功能的改变在糖尿病肾病病理学起重要作用。因此，我们拟采用ZnT8基因敲除小鼠以及ZnT8基因沉默肾小管上皮细胞为模型，探索ZnT8基因结构和功能的变化对肾间质纤维化及肾小管上皮细胞转分化的影响及其相关机制。本研究将为探明锌和ZnT8在糖尿病肾病肾间质纤维化所起的作用及其相关机制，为寻找有效防治糖尿病肾病的关键环节或者分子靶点提供新的科学依据。

糖尿病肾病是糖尿病严重的并发症之一。肾小管病变及肾间质纤维化是糖尿病肾病病理过程中的一个重要环节，而糖尿病和糖尿病肾病患者均存在不同程度的锌缺乏。研究资料业已表明锌缺乏与肺和肝等纤维化密切相关，但对锌缺乏在糖尿病肾病肾间质纤维化所产生的病理作用尚不清楚。近年来研究发现一种锌转运体(ZnT8) 基因DNA多态性以及抗体的功能下降与糖尿病密切相关。我们在前期研究工作中，发现ZnT8在人和大鼠肾小管上皮细胞中表达，很可能它的结构和功能的改变在糖尿病肾病病理学起重要作用。因此，我们拟采用ZnT8基因敲除小鼠以及ZnT8基因沉默肾小管上皮细胞为模型，探索ZnT8基因结构和功能的变化对肾间质纤维化及肾小管上皮细胞转分化的影响及其相关机制。本研究将为探明锌和ZnT8在糖尿病肾病肾间质纤维化所起的作用及其相关机制，为寻找有效防治糖尿病肾病的关键环节或者分子靶点提供新的科学依据。