芪参方肠道滞留成分通过调节短链脂肪酸Olfr78 /Gpr41肾脏-血管双感受器维系宿主血压平衡的作用机制

As a common chronic cardiovascular disease, the pathogenesis of hypertension involves complex factors including gene and environment, which remain to be fully explored. The latest research reveals a new mechanism of homeostasis of host blood pressure that is regulated by a pair of SCFA-sensing blood pressure receptors Olfr78 and/Gpr41 in the renal and vascular walls, regulated by the intestinal microflora metabolites. Chinese medicine has a rich clinical basis and proven effect on the treatment of hypertension with the principle of "reinforcing deficiency and reducing the reality and adapting Yin and Yang". Therefore, we put forward the scientific hypothesis of "intestinal retention components of the Qi-benefiting/Blood-activating compound Qishen formula maintain blood pressure balance through intestinal microflora metabolites, which coordinate the expression and function of SCFA-sensing Olfr78/Gpr41 dual receptors in intestine, kidney and blood vessels. Based on a solid research foundation of this team on the "blood-activating components in Chinese medicine, this project aims to utilize rat renal (RHR) and vascular (SHRsp) hypertension models to investigate the interactions of “Qi-benefiting” intestinal retention components of Qishen formula with intestinal SCFA at the levels of the whole animal, intestinal / kidney / vascular targeting organs and molecular G-protein coupled receptor signaling system, exploring their differential regulation on kidney Olfr78 and vascular wall Gpr41 dual blood pressure receptors. The goal of the research is to reveal the vascular biology connotation of “Qi”, and the mechanism of “Qi-benefiting” active ingredients in the maintenance of blood pressure homeostasis through the intestinal microflora metabolites in renovascular hypertension.

高血压为一种常见慢性心血管疾病，致病机制包含遗传、环境等多重因素，至今仍有待深入探究。最新研究揭示了肾脏和血管壁中一对短链脂肪酸感受器Olfr78/Gpr41与血压调节的关系。中医药以“补虚泻实，适其阴阳” 为原则治疗高血压病具有良好的临床疗效。因此我们提出“益气活血复方芪参方中肠道滞留成分通过菌群代谢产物协调肠、肾、血管Olfr78/Gpr41表达和功能，维系血压平衡”这一科学假说。基于本团队前期对“活血”中药活性成分的坚实研究基础，本课题拟以肾性和血管性高血压大鼠为模型，探讨芪参方中肠道滞留的“益气”活性成分与肠道短链脂肪酸的相互作用，在整体动物、肠/肾/血管靶器官和G蛋白偶联受体分子信号通路三个水平系统探究其对Olfr78和Gpr41血压感受器受体的差异调节，揭示 “益气”功能的血管生物学内涵和“益气”活性成分通过肠道菌群代谢产物差别影响肾性和血管性高血压大鼠血压平衡的作用机制。

益气活血类中药芪参方的缺血性心脏疾病临床疗效明确，但对心脑血管综合疾病如高血压的疗效和作用机制尚不清楚。作为按中医药配伍理论构建的组分中药代表，芪参方对区分不同高血压证候的辨证论治理解也具有重要意义。本课题以肾性（salt- sensitive）和血管性（SHR）高血压大鼠为模型，探讨芪参方及其肠道滞留的成分与肠道短链脂肪酸的相互作用，在整体动物、高血压靶器官和血压调节分子信号通路三个水平系统探究“益气”/“活血”功能的血管生物学内涵和“益气”/“活血”活性成分通过肠道菌群代谢产物差别影响肾性和血管性高血压大鼠血压平衡的作用机制。我们发现，1）芪参方在肾性和血管性高血压大鼠中均具有明显降压作用，但机制不同；2）芪参方可以显著降低高盐饮食引起的血压升高，减轻肾脏的组织病理学变化，纤维化和胶原沉积，并改善肾脏肥大指数以及血清和尿中肌酐和白蛋白的含量，该效果与其抑制Adra1d和促进Sik1表达有关；3）芪参方显著改善高盐诱导血压升高引起的心脏舒张功能障碍，减轻心肌病理变化、纤维化和胶原沉积，减弱心脏肥大指数，该心脏作用可能与其抑制Periostin等纤维化相关基因的表达有关；4）芪参方的入血成分和肠道滞留成分对血压调节的靶器官具有不同作用，尤其是“益气”/“活血”组分对高血压发生的重要诱导因子脑卒中防治通过差异机制实现；5）芪参方及其肠道滞留成分有效降低SHR大鼠的高血压，改善肠系膜受损和紧密连接蛋白（ZO-1）表达降低，而抗菌素能部分逆转该作用；6）SHR大鼠的肠道菌群谱和短链脂肪酸谱均发生明显变化，而芪参方及其肠道滞留成分对SHR大鼠的血压调节作用具有菌群和其产生的短链脂肪酸依赖性，其中异丁酸、异戊酸和己酸可能是介导该作用的关键介质分子。靶器官相应短链脂肪酸GPCR血压感受器表达水平仍有待进一步验证。综上，组分中药芪参方的入血成分和肠道滞留成分通过多成分多靶点多通路的特点发挥降低肾性和血管性高血压及其导致的心肾损伤作用。