INDOXYL SULFATE AND CARDIO-RENAL SYNDROME; THE ROLE OF ARYL HYDROCARBON RECEPTOR


Toshisuke Morita, M.D., Ph.D., Toho University Omori Medical Center, Ota-ku, Tokyo, Japan

The aim of this lecture is to discuss research involving the ligand of the aryl hydrocarbon receptor (AhR) and their role in cardio-renal syndrome. AhR is a ligand-activated nuclear receptor/transcription factor belonging to the basic helix-loop-helix/per-AhR nuclear translocator-Sim family of proteins. While activation of the AhR with ligands is well known to regulate drug metabolisms, cancer growth and development of organs in fetal life, more recently an interesting pathophysiological role of AhR has been reported indicating that AhR also controls vascular function. Accelerated senescence and inflammation with enhanced oxidative stress in cardiovascular system are observed in chronic kidney disease (CKD) patients and such correlation between CKD and cardiovascular disease (CVD) is recognized as cardio-renal syndrome. Indoxyl sulfate (IS), one of the protein-bound uremic toxins, is metabolized in the liver by using tryptophan-derived indole produced by tryptophanase in intestinal bacteria and normally excreted into urine, however, reduced renal clearance elevates serum level of IS, which in turn, enhances oxidative stress in CKD patients. Recently, we reported that IS functions as a ligand of AhR in endothelial cells, leading to enhanced ROS production via NADPH oxidase. Furthermore, we revealed that IS-induced activation of AhR causes vascular inflammation as well as premature senescence in endothelial cells, indicating IS influences endothelial function via AhR signaling pathway. These findings have opened new avenues of research on the possibility of targeting the AhR to treat cardio-renal syndrome. In the lecture, I will show our recent data indicating the importance of AhR signaling pathway in cardio-renal syndrome.