title: Differential effect of COX1 and COX2 inhibitors on renal outcomes following ischemic acute kidney injury.
abstract: OBJECTIVE
  We have previously shown that 1 mg/kg indomethacin improves expression and functionality of renal organic anion transporters Oat1 and Oat3 after renal ischemia and furthermore improves renal outcome after ischemia. As we detected differential effects of COX1 or COX2 inhibitors on organic anion transport after ischemia and reperfusion in culture, we investigated the effect of the SC560 (COX1 inhibitor) and SC58125 (COX2 inhibitor) on expression of Oat1/3 and renal outcome after ischemic acute kidney injury (iAKI).
  
  
  METHODS
  iAKI was induced in rats by bilateral clamping of renal arteries for 45 min. SC560 or SC58125 (1 mg/kg each) were given intraperitoneally as soon as reperfusion started. Sham-treated animals served as controls. Oat1/3 were determined by qPCR and Western blot. Glomerular filtration rate (GFR), p-aminohippurate (PAH) clearance and PAH extraction ratio was determined. All parameters were detected 24 h after ischemia. Renal plasma flow was calculated.
  
  
  RESULTS
  In clamped animals SC560 (COX1 inhibitor) restored expression of Oat1/3, as well as renal perfusion. Additionally, SC560 substantially improved kidney function as measured by GFR. Application of the COX2 inhibitor SC58125 did not exert these beneficial effects.
  
  
  CONCLUSIONS
  Our study indicates that COX1 inhibitor SC560 applied after ischemia prevents ischemia-induced downregulation of Oat1/3 during reperfusion and has a substantial protective effect on kidney function. Whether and to what particular extent this apparent improvement of function is mechanistically due to beneficial effects on tubular function, renal perfusion or glomerular filtration will be the scope of future studies.
authors.affiliation: Klinik für Anästhesie und Operative Intensivmedizin, Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Ariane
authors.initials: A
authors.lastname: Bischoff
authors.forename: Michael
authors.initials: M
authors.lastname: Bucher
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
authors.forename: Christoph
authors.initials: C
authors.lastname: Sauvant
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects; D027362:Organic Anion Transport Protein 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D011720:Pyrazoles; D012333:RNA, Messenger; C115461:SC 560; C421043:Slc22a6 protein, rat; C114338:organic anion transport protein 3; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D010130:p-Aminohippuric Acid