Elucidation of the cyclooxygenase-dependent kidney development in the mouse

镇痛药（非甾体类镇痛药）是最常用的药物之一。它们靶向一种或两种形式的环氧合酶，称为考克斯-1和考克斯-2。妊娠期考克斯-2的抑制导致人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添加了重要的拼图。我们发现，临床使用的镇痛药对肾脏发育的影响程度各不相同，最严重的肾损害是纳曲林（考克斯-1/考克斯-2抑制剂）和罗非昔布（考克斯-2抑制剂）。此外，考克斯-2基因浓度和考克斯-2活性受损程度也不同程度地影响肾发育。在小鼠中，我们将考克斯-2抑制的最敏感时间窗定义为出生后P4至P8天。在此期间，观察到考克斯-2以及线粒体PGE 2合酶1型（mPGES-1）的诱导与肾PGE 2合成的增加相关。我们证明，PGE 2形成后，肾素血管紧张素醛固酮系统（RAAS）被激活与连续的NaCl重吸收，这两个过程对正常肾脏发育至关重要。因此，给予考克斯-2-/-幼仔血管紧张素II受体（AT 1）激动剂可挽救肾发育缺陷，并长期改善肾功能。关于考克斯-2依赖性肾脏发育仍有一些问题需要澄清：哪个介导系统负责最初的考克斯-2/mPGES-1/PGE 2诱导？我们建议使用皮质类固醇。PGE 2通过4种类型的受体EP 1、EP 2、EP 3和EP 4发出信号，这些受体能够影响不同的信号系统，对肾脏发育产生不同的影响。将阐明不同受体类型的作用。提示，旁边的PGE 2也PGI 2和它的IP受体是一个重要的信号分子在这种情况下？PGI 2系统的作用以及肾脏或全身形成的PGE 2/PGI 2是否决定肾脏发育的问题将是我们研究的主题。此外，还将研究考克斯-2在出生前和出生后表达对肾发生的作用。阐明这些问题将使我们扩大对考克斯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止痛药引起的副作用。

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.