蛋白磷酸酶pp6调控调节性T细胞代谢重塑在高血压肾损伤中的作用机制

调节性T细胞(Tregs)在高血压肾损伤中作用关键，代谢重编程调控其功能，而如何启动Tregs代谢模式变化的内在机制尚不清楚。近期我们发现：血管紧张素II诱导高血压肾损伤中pp6病理性低表达，基因剔除pp6抑制Tregs分化和免疫抑制功能并偶联代谢模式从氧化磷酸化向糖酵解转变，加重肾损伤；pp6与线粒体功能蛋白Tid1的去磷酸化相关联；原创性肽miPEP31靶向上调pp6。推测pp6低表达减弱Tid1去磷酸化致线粒体功能受损，驱动Tregs代谢模式的改变参与调控生物学功能。因此，本项目拟以Tregs能量代谢模式为切入点探索：1、pp6去磷酸化Tid1调控线粒体功能的生化基础；2、Tid1调节Tregs代谢重编程和功能在高血压肾损伤中的机理；3、miPEP31治疗高血压肾损伤的效果及机制。明晰去磷酸化酶、代谢重塑、miPEP31、肾纤维化之间的关系，为逆转高血压肾损伤提供新思路。

Regulatory T cells (Tregs) play an important role in hypertensive renal injury, and metabolic reprogramming regulates the immunosuppressive function of Tregs, however, the underlying regulators of the metabolic reprogramming of Tregs remain unclear. Our recent studies found that: The expression of pp6 was pathologically decreased in Angiotension II (Ang II)-induced hypertensive injury renal tissues, and the genetic deletion of pp6 not only inhibited Tregs differentiation and immunosuppressive function but also undergoesed a shift from oxidative phosphorylation to aerobic glycolysis, and aggravated renal injury. We further found pp6 was associated with dephosphorylation of mitochondrial functional protein Tid1, the peptide miPEP31 identified by our group upregulated pp6. It is speculated that the loss of pp6 in Tregs attenuates the dephosphorylation of Tid1, resulting in impaired mitochondrial function, driving the metabolic alteration of Tregs and participating in the regulation of the biological function of Tregs. Therefore, taking the energy metabolism patteren of Tregs as the pointcut, our project intends to investigate: 1. Biochemical mechanism of pp6-mediated Tid1 dephosphorylation on mitochondrial function and metabolism; 2. The role of Tid1-mediated Tregs metabolic reprogramming and immunosuppression in hypertensive renal injury; 3. Whether miPEP31 harbours a therapeutic potential in hypertensive renal injury. This study would elucidate the relationship among phosphatase, metabolic remodeling, miPEP31, renal fibrosis. Taken together, these findings may provide a new target for the prevention and treatment of renal injury in hypertension.