#2884 Dose-dependent EGR1 expression in the rat renal medulla after chronic NSAID treatment

Abstract Background and Aims Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in clinical medicine. Chronic use of NSAIDs is associated with reduced renal medullary blood flow, potentially causing severe and irreversible damage including papilla necrosis. We have previously demonstrated that chronic hyperosmolar injury in the renal medulla induces the expression of pro-fibrotic TGF-beta1 and EGR1. However, the impact of chronic NSAID treatment on EGR1 and pro-fibrotic factors in renal cortex and medulla remains unexplored. Thus, we aimed to analyze the effects of chronic NSAID treatment in the rat renal medulla. Method Male Wistar rats (250-260 grams) were orally treated twice daily for two weeks with various NSAIDs: indomethacin (IND, 2 mg/kg), naproxen (NAP, 10 or 20 mg/kg), celecoxib (CEL, 10 and 30 mg/kg), or vehicle (1% hydroxyethylcellulose). Left kidney was removed for histology and immunohistochemistry, the right kidney medulla was separated for mRNA analysis. Kruskal-Wallis test was performed for statistical analysis. Results NSAIDs caused significant tubular dilatation in all treated groups except IND. CEL (10, 30 mg/kg) and NAP (10 mg/kg) markedly increased epithelial atrophy. NAP 10 and 30 mg/kg induced a dose-dependent, 2-fold and 3.2-fold TIMP1 mRNA over-expression, respectively. Only NAP 20 mg/kg induced significant, 2.5-fold EGR1 mRNA expression. Both IND and CEL increased a 2-fold EGR1 protein expression in the medulla, but NAP induced a dose-dependent 5- and 10-fold increase of EGR1 protein. Conclusion Our study show that EGR1 and TIMP1 might play an important role in the development of NSAID induced tissue injury in the rat renal medulla. Further studies are needed to shed light on the molecular pathogenesis.