Role of mPGES1 in regulation of kidney function

描述（由申请人提供）：脂质介质前列腺素（PG）E2在肾脏中具有多种作用，影响肾素释放、血管张力和上皮功能。PGE 2激活肾素-血管紧张素系统的结果与其对肾血管系统和上皮细胞的作用直接相反，后者导致血管舒张和尿钠排泄。在特定的肾脏微环境中调节PGE 2水平可以提供控制这些明显不同的作用的机制。我们研究的长期目标是确定负责肾脏中PGE 2终末合成的基因，并确定其调节肾功能的能力。到目前为止，已经确定了两个微粒体PGE合成（mPGESI和mPGES 2），从内过氧化物产生PGE 2，我们假设mPGESI和mPGES 2有离散的功能，以调节区域PGE 2的合成，提供了一种机制，独立控制PGE 2在肾脏的矛盾行动。为了验证这一假设，我们将使用基因靶向小鼠来研究mPgesI和mPges 2基因对肾脏PGE 2生成、钠和水排泄以及血压调节的贡献。这些研究将为前列腺素调节肾功能和血压提供新的见解。

DESCRIPTION (provided by applicant): The lipid mediator prostaglandin (PG) E2 has diverse actions in the kidney affecting renin release, vascular tone, and epithelial functions. The consequences of renin-angiotensin system activation by PGE2 are in direct opposition to its effects on renal vasculature and epithelia that lead to vasodilation and natriuresis. Regulation of PGE2 levels within specific renal microenvironments could provide a mechanism to control these apparently disparate actions. The long-term goal of our research is to identify genes responsible for the terminal synthesis of PGE2 in the kidney and define their capacities to regulate renal functions. To date, two microsomal PGE syntheses (mPGESI and mPGES2) have been identified that generate PGE2 from endoperoxides, and we hypothesize that mPGESI and mPGES2 have discrete functions to regulate regional synthesis of PGE2, providing a mechanism for independent control of the paradoxical actions of PGE2 in the kidney. To test this hypothesis we will use gene-targeted mice to investigate the contribution of the mPgesI and mPges2 genes to renal PGE2 generation, sodium and water excretion, and blood pressure regulation. These studies will provide new insights into prostanoid regulation of renal function and blood pressure.