Cyclooxygenase‐2 Regulates the Renal Expression of Indoleamine 2,3‐dioxygenase

Abstract

Chronic kidney disease (CKD) affects approximately 10% of the population. In CKD patients, the majority of metabolic pathways are in disarray, which most likely contributes to the wide variety of comorbidities observed in these patients. However, few studies have focused on the unique regulatory aspects of enzyme systems during CKD development and progression. The cyclooxygenase‐2 (COX‐2)/prostaglandin (PG) system plays a dominant role in the progression of renal injury. Interestingly, it has been shown that the COX‐2/PG system modulates the activity of indoleamine 2,3‐dioxygenase (IDO) in tumors. Catabolism of tryptophan by IDO gives rise to numerous biologically active metabolites implicated in CKD progression. Therefore, the aim of this project is to explore the interplay between the COX‐2 and IDO enzyme systems during renal injury.We studied the gene expression of IDO, COX‐2 as well as several fibrosis and inflammatory markers in human and murine precision‐cut kidney slices (PCKS) and COX‐2 KO mice. Furthermore, we evaluated the gene expression profile after treatment with butaprost, an EP2 receptor agonist, in hPCKS and following treatment with SC‐236, a selective COX‐2 inhibitor, in mPCKS.Our results demonstrated that IDO gene expression was markedly increased in both human and mouse PCKS during the first 24h of culturing, after which levels dropped again. This expression profile was similar to the gene expression of various cytokines (e.g. IL‐6 and CXCL1), suggesting a potential pro‐inflammatory role of IDO. In addition, in COX‐2 KO animals, constitutive gene expression of IDO was increased as compared to wild‐type mice, and the knockout animals appeared to be more prone to renal fibrosis. Moreover, treatment with butaprost suppressed IDO gene expression, while exposure to SC‐236 induced IDO mRNA expression as well as the gene levels of IL‐6 and IL‐8.Taken together, it appears that COX‐2 suppresses IDO gene expression. In addition, our findings suggest a potential pro‐inflammatory role of IDO. However, the precise role of IDO in CDK development and progression requires further study.Support or Funding InformationThis work was kindly supported by Lundbeckfonden, grant number R231‐2016‐2344.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.