Role of mPGES1 in regulation of kidney function

描述(由申请人提供)：脂质介体前列腺素(PG)E2在肾脏中有不同的作用，影响肾素的释放、血管紧张性和上皮功能。PGE2激活肾素-血管紧张素系统的后果与其对肾血管和肾上皮细胞的影响直接相反，后者导致血管扩张和钠尿。在特定的肾脏微环境中调节PGE2水平可以提供一种机制来控制这些明显不同的行为。我们研究的长期目标是确定在肾脏中负责PGE2最终合成的基因，并确定它们调节肾功能的能力。到目前为止，已经确定了两种微粒体PGE合成途径(mPGESI和mPGES2)，它们可以从过氧化物质中产生PGE2，我们假设mPGESI和mPGES2具有独立的功能，调节PGE2的区域性合成，为独立控制PGE2在肾脏中的矛盾作用提供了一种机制。为了验证这一假设，我们将使用基因靶标小鼠来研究mPgesI和mPges2基因对肾脏PGE2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对肾功能和血压的调节提供新的见解。

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.