动静脉瘘（AVF）是终末期肾功能衰竭（ESRD）血液透析（HD）患者的生命线。3型钠依赖的磷转运蛋白-1（PiT-1）介导的血管平滑肌细胞（VSMCs）去分化增殖/转分化参与HD-AVF失功的发生，但调节机制不清。文献报道，β连环蛋白调节PiT-1核转录。我们前期研究发现：ESRD小鼠血管血清糖皮质激素诱导激酶3（SGK3）表达增加；SGK3调节β连环蛋白及PiT-1的表达和活性；SGK3与PiT-1相互作用且PiT-1上有SGK3的磷酸化保守序列。由此我们提出SGK3通过调节PiT-1转录和磷酸化参与HD-AVF失功这一假说。为验证上述假说，本项目拟获得SGK3/β连环蛋白调节PiT-1转录的可靠证据；证实SGK3直接磷酸化并调节PiT-1功能；在细胞和整体水平观察SGK3调节的PiT-1在VSMCs去分化增殖/转分化及AVF失功中的作用。本研究将为防治HD-AVF失功提供新的分子药靶。

Arteriovenous fistula (AVF) is the lifeline of the end-stage renal failure (ESRD) hemodialysis (HD) patients. Proliferation and transdifferentiation of vascular smooth muscle cells (VSMCs), mediated by Type 3 sodium-phosphate transporter-1 (PiT-1), is involved in the development of HD-AVF dysfunction, but the detailed molecular mechanisrm is not very clear. Previous reports showed that β-catenin regulated PiT-1 transcripition. Our preliminary experiments revealed that SGK3 was highly expressed in blood vessel of ESRD mice; SGK3 participated in β-catenin expression and regulated the expression and activity of PiT-1; SGK3 interacted with PiT-1; and there was a SGK3 phosphorylated motif located on PiT-1 protein. Thus we speculated that SGK3-mediated PiT-1 transcripition and phosphorylation was involved in the development of HD-AVF dysfunction. In order to verify this hypothesis, we intend to demostrate that SGK3/β-catenin signaling pathway participates in regulating PiT-1 transcripition; and that SGk3 could directly phosphorylate PiT-1. we also try to explore the role of SGK3-triggeed transcripitional and phosphorylation of PiT-1 on the proliferation and transdifferentiation of VSMCs in vitro , and on the dysfunction of HD-AVF in vivo. The expecting results will help us set up new molecular drug targets for prevention and therapy of HD-AVF dysfunction.