Prostaglandin E2 and Regulation of Kidney Function

描述（由申请人提供）：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。花生四烯酸通过磷脂酶、环加氧酶和PGE合成酶的连续作用合成PGE2。到目前为止，已经确定了两种微粒体PGE2合成酶（mPGES1和mPGES2）可以高亲和力和特异性地从内过氧化物中生成PGE2。这些酶有不同的序列和调节模式。虽然mPGES1和mPGES2在肾脏中的功能尚未明确，但我们的初步研究表明：(1)mPGES1和mPGES2在肾脏中都有高表达，(2)在缺乏mPGES1的情况下可以检测到肾脏中PGE2的合成，(3)mPGES1并不能解释PGE2在肾脏或肾外组织中的所有作用。基于这些数据，我们假设mPGES1和mPGES2具有调节PGE2区域合成的离散功能，为PGE2在肾脏中的矛盾作用提供了一种独立控制机制。合成后，PGE2迅速代谢。我们之前发现15-羟基前列腺素脱氢酶（15-PGDH）是体内PGE2代谢的主要途径，其作用对出生时动脉导管的重塑至关重要。然而，15-PGDH在肾脏中的生理作用尚未得到证实。在初步研究中，我们发现15- pgdh缺陷小鼠肾素mRNA表达增强，血压升高。因此，我们假设15-PGDH是消除PGE2肾脏作用的关键途径。在肾脏中，15- PGDH的主要作用是调节肾小球近器（JGA）中PGE2的活性。利用小鼠模型，我们将通过实现以下具体目标来定义肾脏中调节PGE2活性的基因的功能：1。目的：鉴定PGE2通路中控制肾素表达和释放的基因。2. 目的探讨mPGE合成酶对肾功能的调节作用。3. 确定15-PGDH代谢PGE2对肾功能的影响。

DESCRIPTION (provided by applicant): Prostaglandin (PG) E2 has diverse actions in the kidney affecting renin release, vascular tone, and epithelial functions. PGE2 is synthesized from arachidonic acid by the sequential actions of phospholipases, cyclooxygenases, and PGE synthases. To date, two microsomal PGE synthases (mPGES1 and mPGES2) have been identified that generate PGE2 from endoperoxides with high affinity and specificity. These enzymes have different sequences and patterns of regulation. While the functions of mPGES1 and mPGES2 in the kidney have not been defined, our preliminary studies indicate that: (1) mPGES1 and mPGES2 are both highly expressed in the kidney, (2) renal PGE2 synthesis can be detected in the absence of mPGES1, and (3) mPGES1 does not account for all of the actions of PGE2 in the kidney or in extra-renal tissues. Based on these data, we hypothesize that mPGES1 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. After its synthesis, PGE2 is rapidly metabolized. We previously found that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the primary pathway for PGE2 metabolism in vivo and that its actions are essential for remodeling the ductus arteriosus at birth. However, a physiological role for 15-PGDH in the kidney has not been demonstrated. In preliminary studies, we showed that renin mRNA expression is enhanced and blood pressures are elevated in 15-PGDH-deficient mice. We therefore posit that 15-PGDH is a critical pathway for extinguishing the renal actions of PGE2. In the kidney, the dominant effect of 15- PGDH is to regulate the activity of PGE2 at the juxta-glomerular apparatus (JGA). Using mouse models, we will define the functions of the genes that regulate the activity of PGE2 in the kidney by carrying out the following specific aims: 1. To identify the genes in the PGE2 pathway controlling renin expression and release. 2. To define the capacity of mPGE synthases to modulate kidney function. 3. To define the impact of PGE2 metabolism by 15-PGDH on renal functions.