环氧化酶下游通路对肾血流的调控及其对肾缺血再灌注损伤的影响与机制

Endothlial dysfunction plays an important role in renal ischemia/reperfusion injury. We have found that prostanoids produced by cyclooxygenase (COX) metabolic pathway, such as prostacyclin (PGI2), can act on the downstream thromboxane A2 receptor (TP receptor) and prostaglandin E2 receptor 3 (EP3 receptor) to mediate vasocontraction, which counteracts the dilation effect of PGI2 receptor (IP receptor). Our preliminary data showed that the contraction evoked by PGI2 in renal artery of TP knockout (TP-/-) mice was much higher than that in aorta, and EP3 antagonism abolished the contraction. This finding prompted us to hypothesize that there is higher expression of EP3 receptors in renal vessels, which regulate vasomotor function together with TP and IP receptors.It has been reported that oxidative stress causes tyrosine nitration of PGI2 synthase to decrease its activity. We further hypothesize that the production of PGI2 is decreased during I/R injury with accordingly increased production of other prostaglandins, which act on both TP and EP3 receptor to aggravate endothelial dysfunction, and that inhibiting the effects of TP and EP3 receptors ameliorates endothelial dysfunction, increases renal blood flow, and therefore protects the kidey against I/R injury. Therefore, this project will utilize models such as TP-/-EP3-/- mice, together with other physiological, pathophysiological and biochemical methods to substantiate our above hypotheses. We aim to clearly elucidate the mechanism of the downstream receptors of the COX pathway to regulate vasomotor function of renal vessels, and to find out the effect of the intervention of those receptors on renal I/R injury. Our results are expected to provide novel insights into the regulation of renal vascular function, as well as the pathological and pathophysiological mechnisms of related renal diseases, which could provide potential therapeutic target information for the prevention or treatment of the diseases.

血管内皮功能失调在肾脏I/R损伤中扮演重要角色。我们发现环氧化酶（COX）代谢产物PGI2等可作用于下游TP与EP3受体引起血管收缩，并对抗IP受体介导的舒张。初步实验显示，PGI2所引起的TP敲除小鼠肾动脉的收缩比主动脉要强，且可被EP3拮抗剂所抑制。由此我们提出肾脏动脉EP3受体相对高表达，与IP及TP共同调控血管功能。氧化应激可使PGI2合成酶硝基化，我们进一步设想：I/R损伤中血管PGI2生成减少，其它前列腺素类增多，作用于TP与EP3而加重内皮功能失调；抑制两者的效应可改善内皮功能、增加血流灌注，对肾脏I/R损伤起保护作用。本项目拟利用TP与EP3双敲小鼠等，采用生理、病理生理、生物化学等方法确证上述假说，以确定COX通路下游受体对肾血管功能的调控机制，及其对I/R损伤的影响及分子机制。结果将为肾血管功能调控及相关疾病的机制提供新的理论和实验依据，并为其防治提供新的干预靶点信息。

环氧化酶（COX）产物PGI2与PGE2等均可作用于血栓素A2受体（TP）和/或PGE2受体亚型EP3，而COX下游通路对肾血管的调控及在急性肾损伤中的作用与机制尚不清楚。本项目利用TP与EP3双敲小鼠、骨髓移植嵌合体小鼠、以及髓系细胞条件敲除EP3小鼠等，采用生理、病理生理、生物化学等方法以探明以上问题。本项目发现肾脏动脉EP3受体相对高表达，与IP及TP共同调控血管功能.I/R损伤中肾脏PGE2与PGI2生成增加，抑制环氧化酶下游EP3的效应可通过抑制炎症而减少坏死性凋亡，从而打破坏死-炎症这一恶性循环、对肾脏I/R损伤起到保护作用。而且，本项目发现，与其它细胞类型中的EP3相比，髓系细胞中的EP3在介导肾脏I/R损伤中起主导作用。结果将为肾血管功能调控机制提供新的理论和实验依据，并为急性肾损伤相关疾病防治提供新的干预靶点信息。