Elucidation of the cyclooxygenase-dependent kidney development in the mouse

• Applicant: Professor Dr. Rolf Michael Nüsing
• Subject Area: Pharmacology
• Term: from 2007 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 42615255

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.

• DFG Programme: Research Grants