Coordinated Regulation of Dimethylarginine Dimethylaminohydrolase-1 and Cationic Amino Acid Transporter-1 by Farnesoid X Receptor in Mouse Liver and Kidney and Its Implication in the Control of Blood Levels of Asymmetric Dimethylarginine

Abstract

Asymmetric dimethylarginine (ADMA) is a potent endogenous inhibitor of endothelial nitric-oxide synthase (eNOS), and increased plasma concentrations of ADMA have been regarded as a risk factor for a number of cardiovascular diseases. Circulating ADMA is largely taken up by liver and kidney via system y(+) carriers of the cationic amino acid (CAT) family and subsequently metabolized by dimethylarginine dimethylaminohydrolases (DDAHs). As such, agents targeted at enhancing ADMA metabolism may prove to be useful in the prevention and/or treatment of various types of cardiovascular disease. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and plays an important role in the maintenance of cholesterol and bile acid homeostasis. We report here that treatment of mice with an FXR agonist 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole; GW4064) led to increased expression of DDAH-1 and CAT-1 in both liver and kidney. In cultured human hepatocytes and kidney proximal tubular epithelial cells, GW4064 increased CAT-1 expression, and this was associated with a significant increase in the cellular uptake of ADMA. Promoter analyses suggest that CAT-1 is a likely target of FXR, and a functional FXR response element was found in the promoter region of CAT-1 gene. These data suggest that FXR may play an important role in regulating blood levels of ADMA via coordinated regulation of DDAH-1 and CAT-1 in liver and kidney.