过氧化物酶体增殖剂激活受体γ (PPAR-γ) 在糖、脂代谢中发挥重要作用，其人工合成配体在临床上广泛用于糖尿病的治疗，然而长期服用会引起水钠潴留，增加心血管疾病发生的危险。最近，我们用高脂诱导CYP4F2转基因小鼠糖尿病，发现高脂显著改变PPAR-γ和Na+-K+-2Cl-共转运体（NKCC2）表达，推测NKCC2是PPAR-γ调节肾脏水钠重吸收的重要靶点之一。因此，本项目拟借助肥胖Zucker大鼠，辅助细胞模型，以NKCC2为靶基因，从3个方面揭示PPAR-γ调节NKCC2的作用机制：① 20-HETE在PPAR-γ调节NKCC2中的作用；②PPAR-α诱导20-HETE合成对PPAR-γ引起的水钠潴留的作用；③PPAR-γ在转录水平对NKCC2基因表达的作用。本研究将深入阐述PPAR-γ通过NKCC2引水钠潴留的作用机制，为临床合理用药治疗2型糖尿病，避免不良反应的发生奠定理论基础。

Peroxisome proliferator-activated receptors γ (PPAR-γ) plays an important role in the glucose and lipid metabolism, its ligands are highly benefical in the treatment of type Ⅱ diabetes. However, they are also associated with fluid retention, and give rise to cardiovascular disease. Recently, we fed CYP4F2 transgenic mice high-fat diet to build diabetes model, and found that high fat significantly changed the expression of PPAR-γand Na+-K+-2Cl- cotransporter（NKCC2）protein, suggesting that NKCC2 may be an important target to PPAR-γ. Therefore, the purpose of this project is to explore the possibly molecular mechanisms of PPAR-γ regulating on NKCC2. With obese Zucker rat model and cultured cells, we will study from 3 aspects: ①20-HETE plays an important role on NKCC2 regulated by PPAR-γ. ②PPAR-α can relieve fluid retention indued by PPAR-γ through the increase of 20-HETE. ③PPAR-γ transcriptional regulate NKCC2 expression. This research will illustrate the molecular mechanism that PPAR-γinduces fluid retention through NKCC2, which will provide a novel strategy for clinical treatment of type Ⅱ diabetes.