糖尿病肾病(DN)是导致肾衰竭的首要病因，缺乏有效治疗手段，肾小管间质纤维化程度决定了DN的预后。SHIP2是PI3K/Akt通路的重要负性调节因子，参与胰岛素信号通路，在DN中作用不清。我们前期研究首次发现：DN中SHIP2表达上调，与肾功能下降相关；SHIP2通过影响Akt活化而致肾小管上皮细胞分泌细胞外基质增多；SHIP2参与调控Hippo通路。抑制SHIP2有望成为治疗DN的新靶点，但机制尚需深入研究。Hippo是新发现的控制器官大小、细胞增殖和分化的关键信号通路。因此提出假说：SHIP2高表达导致肾小管上皮细胞活化，通过调控Hippo通路而加重DN肾小管间质病变。本课题拟进一步研究：1)明确SHIP2在DN中对肾小管上皮细胞活化和功能的影响及机制。2)探讨SHIP2调控Hippo通路机制。3)评估SHIP2抑制剂在DN治疗中的转化前景。旨在建立以SHIP2为靶向的DN治疗新策略。

Diabetic nephropathy (DN) is one of the leading causes of end-stage kidney disease, with poor effective treatment. SH2-containing inositol phosphatase 2 (SHIP2) is a phosphatase that catalyse dephospharylation at the 5-position of phosphatidylinositol 3,4,5-trisphosphate. SHIP2 is an important negative regulator in PI3K/Akt pathway. SHIP2 interacts with proteins involved in insulin signaling, cytoskeletal function (endocytosis, adhesion, proliferation and apoptosis) and immune system function. However, the role of SHIP2 in DN is not limited to its interaction with insulin signal. Much remains unknown about the roles of SHIP2 and possible future directions for research. Our preliminary data showed that SHIP2 was significantly upregulated in tubular epithelial cells in DN renal biopsy tissue, and SHIP2 expression correlated inversely with renal function. Moreover, in vitro study showed that SHIP2 inhibitor ameliorated the high glucose-induced extracellular matrix protein upregulation and p-Akt reduction in cultured mouse proximal tubule epithelial cell line. The elucidation of the role of Hippo pathway has provided new insights in understanding the regulation of cell proliferation, cell death, and cell differentiation to control organ size. Yes-associated protein (YAP) is a transcriptional regulator in Hippo pathway. YAP protein expression and phosphorylation were upregulated in diabetic mouse renal proximal tubule epithelial cells, and involved in epithelial to mesenchymal transition. Furthermore, we also found that inhibition of SHIP2 by using siRNA could downregulated the expression of YAP in cultured proximal tubule epithelial cell, indicating that SHIP2 is involved in the regulation of Hippo pathway. So here we try to study the expression and function of SHIP2 in the mechanism of DN. Furthermore, we are about to examine the possible signaling pathways which SHIP2 could be involved. Finally, we will investigate whether the regulation of SHIP2 is involved in Hippo signaling pathway in DN. Our study may provide a new theoretical and experimental basis for the mechanism of diabetic nephropathy.