FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats

• Published in: PloS one 2013-04, Vol.8 (4), p.e60653
• Main Authors: Ghebremariam, Yohannes T, Yamada, Keisuke, Lee, Jerry C, Johnson, Christine L C, Atzler, Dorothee, Anderssohn, Maike, Agrawal, Rani, Higgins, John P, Patterson, Andrew J, Böger, Rainer H, Cooke, John P
• Format: Article
• Language: English
• Subjects: Acids; Amidohydrolases - genetics; Amidohydrolases - metabolism; Animals; Biology; Blood; Blood pressure; Blood Pressure - drug effects; Cardiomegaly - etiology; Cardiomegaly - pathology; Cardiovascular disease; Chenodeoxycholic Acid - administration & dosage; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - pharmacology; Development and progression; Diabetes; Diet; Endothelium; Gene Expression Regulation - drug effects; Genetic aspects; Homeostasis; Hypertension; Hypertension - drug therapy; Hypertension - etiology; In vivo methods and tests; Insulin; Insulin Resistance; Kidney - drug effects; Kidney - pathology; Kidney Function Tests; Laboratory animals; Liver - drug effects; Liver - metabolism; Male; Medicine; Metabolism; Nitric oxide; Nitric Oxide - metabolism; Nitric-oxide synthase; Organ Size; Oxidative stress; Pharmacology; Physiological aspects; Plasma; Pressure effects; Rats; Receptors, Cytoplasmic and Nuclear - agonists; Regulatory sequences; Risk factors; Rodents; Salts; Sensitivity; Sensitivity analysis; Sensitivity enhancement; Sodium Chloride, Dietary; Toxicology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060653

Genetic and pharmacological studies have shown that impairment of the nitric oxide (NO) synthase (NOS) pathway is associated with hypertension and insulin-resistance (IR). In addition, inhibition of NOS by the endogenous inhibitor, asymmetric dimethylarginine (ADMA), may also result in hypertension and IR. On the other hand, overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes ADMA, in mice is associated with lower ADMA, increased NO and enhanced insulin sensitivity. Since DDAH carries a farnesoid X receptor (FXR)-responsive element, we aimed to upregulate its expression by an FXR-agonist, INT-747, and evaluate its effect on blood pressure and insulin sensitivity. In this study, we evaluated the in vivo effect of INT-747 on tissue DDAH expression and insulin sensitivity in the Dahl rat model of salt-sensitive hypertension and IR (Dahl-SS). Our data indicates that high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls. Our study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.