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Elucidation of the cyclooxygenase-dependent kidney development in the mouse

阐明小鼠环氧合酶依赖性肾脏发育

基本信息

批准号：
42615255
负责人：
Professor Dr. Rolf Michael Nüsing
金额：
--
依托单位：
Institut für Klinische Pharmakologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2007
资助国家：
德国
起止时间：
2006-12-31 至 2023-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/42615255?language=en
关键词：
Elucidation cyclooxygenase dependent kidney development

项目摘要

Analgesic drugs (non steroidal antiinflammatory drugs) are among the most used drugs. They target one or both forms of cyclooxygenase, known as COX-1 and COX-2. Inhibition of COX-2 during gestation causes severe defects in kidney development and function in man and animal. In the recent projects we added important pieces of puzzle to the underlying pathological mechanism. We showed that clinically used analgesic drugs affect kidney development to very varying extent, with most worse kidney impairment by naproxen (COX-1/COX-2 inhibitor) and rofecoxib (COX-2 inhibitor). Further, also COX-2 gene concentration and degree of impaired COX-2 activity affects kidney development to different extents. In mouse, we defined the most sensitive time window for COX-2-inhibition to day P4 to P8 after birth. During this period induction of COX-2, as well as mitochondrial PGE2 synthase type 1 (mPGES-1) is observed associated with increases in renal PGE2 synthesis. We demonstrated that following PGE2 formation the renin angiotensin aldosterone system (RAAS) is activated with consecutive NaCl reabsorption, both processes essential for normal kidney development. In accordance administration of an angiotensin II receptor (AT1) agonist to COX-2-/- pups rescued renal developmental defects and ameliorated kidney function in the long term. Regarding COX-2-dependent kidney development still some questions need to be clarified: Which mediator system is responsible for the initial COX-2/mPGES-1/PGE2 induction? We suggest corticosteroids. PGE2 signals via 4 types of receptors, EP1, EP2, EP3 and EP4 which are able to affect different signaling systems with different effects on kidney development. The role of the different receptor types will be elucidated. Hints are given that next to PGE2 also PGI2 and its IP receptor is an important signaling molecule in this setting? The role of PGI2 system as well as the question whether renally or systemically formed PGE2/PGI2 is determining kidney development will be subject of our research. Furthermore, the role of prenatal next to postnatal expression of COX-2 for nephrogenesis will be investigated. Answering these questions will enable us to enlarge our knowledge on the role of the COX system in kidney development and hopefully help us to obtain an even more extensive picture of side effects caused by use or abuse of analgesic drugs.

镇痛药（非甾体类抗炎药）是最常用的药物之一。它们针对一种或两种形式的环加氧酶，即COX-1和COX-2。COX-2在妊娠期的抑制会导致人类和动物肾脏发育和功能的严重缺陷。在最近的项目中，我们为潜在的病理机制增加了重要的谜团。我们发现临床使用的镇痛药物对肾脏发育的影响程度非常不同，其中萘普生（COX-1/COX-2抑制剂）和罗非昔布（COX-2抑制剂）对肾脏损害最严重。此外，COX-2基因浓度和COX-2活性受损程度也在不同程度上影响肾脏发育。在小鼠中，我们定义了出生后P4至P8天对cox -2抑制最敏感的时间窗口。在此期间，观察到COX-2的诱导以及线粒体PGE2合酶1型（mPGES-1）与肾脏PGE2合成的增加有关。我们证明，在PGE2形成后，肾素血管紧张素醛固酮系统（RAAS）被连续的NaCl重吸收激活，这两个过程对正常肾脏发育至关重要。因此，血管紧张素II受体（AT1）激动剂对COX-2-/-幼犬的长期治疗可挽救肾脏发育缺陷并改善肾功能。关于COX-2依赖性肾脏发育仍有一些问题需要澄清：哪个中介系统负责最初的COX-2/mPGES-1/PGE2诱导？我们建议使用皮质类固醇。PGE2通过EP1、EP2、EP3和EP4 4种受体发出信号，它们能够影响不同的信号系统，对肾脏发育产生不同的影响。不同受体类型的作用将被阐明。提示除了PGE2， PGI2及其IP受体也是一个重要的信号分子。PGI2系统的作用以及PGE2/PGI2是肾脏还是系统形成的决定肾脏发育的问题将是我们研究的主题。此外，将研究产前和产后COX-2表达在肾病发生中的作用。回答这些问题将使我们能够扩大我们对COX系统在肾脏发育中的作用的认识，并有望帮助我们更广泛地了解使用或滥用镇痛药物引起的副作用。