血管紧张素II受体1型阻滞性抗体Anti-ATR保护先兆子痫肾脏及其机制研究

The second loop outside the cell membrane of angiotensin II type 1 receptor (AT1R) is an important site of ligand binding, which has a great influence on the preference of the receptor functional activation. There are AT1-AAs in patients with preeclampsia which can bind with the AT1R extracellular the second loop. AT1 - AA can cause high blood pressure and proteinuria and other pathological conditions through activation of AT1R in preeclampsia patients, which worsen the prognosis of patients. Our research team has developed ATRQβ-001 short peptide vaccine against human AT1R. The specific vaccine antibody which targeted AT1R has significant AT1R inhibition effect and kidney protection. Anti - ATR and AT1 - AA both act on the same epitope sequence (AFHYESQ) of the AT1R,however their biological effects are significantly different. This research will illustrate: 1) Anti-ATR renal protective effect on preeclampsia animal model;2) Anti-ATR and AT1-AA have different combination affinity to the AT1R extracellular second loop specific amino acid residues, thus leading to the differences of AT1R receptor allosteric effect and preference functional effect.

血管紧张素II受体1型（AT1R）细胞膜外第二环是配体结合的重要位点，对受体功能偏向性激活有重要的作用。先兆子痫患者循环中存在针对AT1R胞外第二环的自身激动性抗体（AT1-AA），AT1-AA激活AT1R导致先兆子痫患者高血压及蛋白尿等病理状态，严重恶化患者预后。本研究团队在国际上首次研制出针对于人AT1R的短肽疫苗ATRQβ-001，该疫苗的针对性抗体(Anti-ATR)具有显著的AT1R阻滞效应及肾脏保护作用。Anti-ATR和AT1-AA作用于AT1R相同的表位序列（AFHYESQ），生物学效应却显著不同，本研究将阐明：1）Anti-ATR对先兆子痫肾脏的保护效应；2）Anti-ATR和AT1-AA通过与AT1R胞外第二环序列特定氨基酸残基结合的亲和力的不同，由此导致AT1R受体变构的差异及其偏向性功能效应。

血管紧张素II受体1型（AT1R）细胞膜外第二环是配体结合的重要位点，对受体功能偏向性激活有重要的作用。先兆子痫患者循环中存在针对AT1R胞外第二环的自身激动性抗体（AT1-AA），AT1-AA激活AT1R导致先兆子痫患者高血压及蛋白尿等病理状态，严重恶化患者预后。本研究团队在国际上首次研制出针对于人AT1R的短肽疫苗ATRQβ-001，该疫苗的针对性抗体(Anti-ATR)具有显著的AT1R阻滞效应及肾脏保护作用。Anti-ATR和AT1-AA作用于AT1R相同的表位序列（AFHYESQ），生物学效应却显著不同，本研究阐明：1）Anti-ATR对先兆子痫肾脏的保护效应；2）Anti-ATR和AT1-AA通过与AT1R胞外第二环序列特定氨基酸残基结合的亲和力的不同，由此导致AT1R受体变构的差异及其偏向性功能效应；3）Anti-ATR不影响RUPP先兆子痫模型大鼠的血压；4）抑制RUPP先兆子痫模型大鼠的肾病进展；5）抑制RUPP大鼠肾脏纤维化；6）Anti-ATR对细胞钙离子浓度的影响；7）Anti-ATR不影响G蛋白与AT1R耦联；8）Anti-ATR不影响AT1R受体内化。