肝再生增强因子在糖尿病肾病脂质代谢中的作用与机制探讨

Diabetic nephropathy（DN）is the first leading cause of end-stage renal disease. Characteristic pathological changes of DN are glomerulosclerosis, tubulointerstitial fibrosis and atrophy. Current studies have confirmed that lipid abnormalities in renal tubular cells play an important role in the progression of DN. Augmenter of Liver Regeneration (ALR) is a FAD-dependent sulfhydryl oxidase and is located in the mitochondrial membrane space. It is involved in Mia40-dependent mitochondrial membrane-space transport system. Recently, studies indicated . ALR also involved in energy metabolism, especially in fatty acids β oxidation process. Therefore, we put forward the scientific hypothesis: ALR may be involved in the lipid metabolism of diabetic tubules and may become a therapeutic target for DN. To test this hypothysis, we intends to analyze the expression of ALR in kidney tissue in diabetic mice. Then the expression of ALR in kidney tissue in diabetic mice was attenuated and overexpressed by deno associated virus. The expression of ALR in HK-2 cell would be disturbed by lentivirus. Our observed object was the level of cellular lipid metabolism and the changes of lipid metabolism related protein in in kidney tissue in diabetic mice or in HK-2 cells. This study is a novel try to reveal the mechanism of ALR in the development of diabetic nephropathy and develop treatment strategies for DN.

糖尿病肾病已成为目前终末期肾脏病的首位病因，其特征性的病理改变为肾小球硬化，肾小管间质纤维化及萎缩。目前研究证实肾小管间质病变尤其是肾小管细胞脂质代谢异常在糖尿病肾病进展中发挥了重要作用。肝再生增强因子（Augmenter of Liver Regeneration，ALR）定位于线粒体膜间隙，为FAD依赖的巯基氧化酶，参与了依赖Mia40的线粒体膜间隙蛋白转运，近来的研究发现ALR也参与能量代谢，尤其是脂肪酸β氧化过程，因此我们提出科学假设：ALR参与了糖尿病肾小管脂质代谢过程，可能成为糖尿病肾病的一个治疗靶点。本研究拟从细胞和转基因小鼠入手，首先分析糖尿病肾病时ALR的表达情况，进一步在体外及体内观察减弱及过表达ALR基因后对糖尿病肾病小鼠及高糖处理的HK-2细胞脂质代谢水平的影响及脂质代谢通路相关因子的变化情况，目的在于进一步了解ALR乃至线粒体在糖尿病肾病脂质代谢异常中的作用。

糖尿病肾脏病已成为终末期肾脏病的首位病因，肾小管间质病变在其进展中发挥了重要作用。肾脂肪酸 β 氧化是肾脏的主要能量来源，其变化对糖尿病肾脏病肾小管细胞的纤维化及能量平衡有着重要的影响。23KD肝再生增强因子是一种定位于线粒体膜间隙的巯基氧化酶，既往研究发现其也参与了肝脏脂肪酸 β 氧化过程。本研究通过体内及体外相结合的实验方法来证明ALR参与了糖尿病肾脏病肾小管细胞脂质代谢过程及上皮细胞间质转分化，为进一步理解糖尿病肾脏病发生过程的影响因素及可能的干预措施提供新的理论依据。