糖尿病肾病是全球高发的慢性缺氧代谢性疾病，而肾系膜细胞病变是其主要的病理基础。申请者前期研究发现miR-382对维持系膜细胞的生理状态至关重要。有证据表明：缺氧微环境能诱导miR-382表达上调，并通过PTEN/Akt/mTOR通路促进新生血管的形成；而PTEN/Akt/mTOR通路的激活在高糖诱导的系膜细胞肥大与基质增多病变中发挥重要作用。故有理由推测：缺氧微环境能上调miR-382，激活PTEN/Akt/mTOR通路并引发系膜组织的上述损伤。课题拟采用申请者前期建立的单细胞LBL技术，构建肾系膜细胞3D缺氧微环境，探讨缺氧微环镜对系膜细胞miR-382及PTEN/Akt/mTOR通路的影响；研究高糖诱导的系膜病变与miR-382之间的联系，并明确缺氧微环境对之的叠加效应；解析miR-382可能的调控机制及相关靶基因，并在实验动物中进行验证，以期为糖尿病肾病的临床防治提供新思路和新靶点。

Diabetic nephropathy is a kind of global prevalent chronic metabolic disease accompanying hypoxia, which develops and progresses pathologically basing on renal mesangial cell dysfunctions. Our former research demonstrated that miR-382 is crucial for maintaining of the normal physiological status of renal mesangial cells. Large quantities of studies revealed that miR-382 induced by hypoxia promotes angiogenesis via PTEN/Akt/mTOR signal pathway, while PTEN/Akt/mTOR signal pathway plays an important role in high glucose induced renal mesangial cell hypertrophy and matrix accumulation. Accordingly, we hypothesize that hypoxia could prompt renal mesangial cell hypertrophy and matrix accumulation via up-regulating miR-382 and activating PTEN/Akt/mTOR signal pathway. We intend to explore the influence of hypoxia microenvironment on miR-382 and PTEN/Akt/mTOR signal pathway by constructing three-dimensional hypoxia microenvironment via single cell layer-by-layer assembly technology established by the applicant’s team, investigate the correlation between renal mesangial dysfunctions and miR-382, clear the superposition effect of hypoxia microenvironment on high glucose induced renal mesangial cell hypertrophy and matrix accumulation, analyse the possible regulatory mechanism of miR-382 and its target gene, and further verify in experimental animals, hoping to provide new insight and therapy target of clinical prevention and treatment of diabetic nephropathy in efforts to retard the development and progression of diabetic nephropathy.