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

Abstract

AIMS:

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.

METHODS AND RESULTS:

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.

CONCLUSION:

Our study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.

• Authors: Yohannes T Ghebremariam, Keisuke Yamada, Jerry C Lee, Christine L C Johnson, Dorothee Atzler, Maike Anderssohn, Rani Agrawal, John P Higgins, Andrew J Patterson, Rainer H Böger, John P Cooke
• Journal: PloS one (PLoS One) Vol. 8 Issue 4 Pg. e60653 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23593273 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Cytoplasmic and Nuclear
• Sodium Chloride, Dietary
• obeticholic acid
• farnesoid X-activated receptor
• Chenodeoxycholic Acid
• Nitric Oxide
• Amidohydrolases
• dimethylargininase

Topics

• Amidohydrolases (genetics, metabolism)
• Animals
• Blood Pressure (drug effects)
• Cardiomegaly (etiology, pathology)
• Chenodeoxycholic Acid (administration & dosage, analogs & derivatives, pharmacology)
• Diet
• Gene Expression Regulation (drug effects)
• Hypertension (drug therapy, etiology)
• Insulin Resistance
• Kidney (drug effects, pathology)
• Kidney Function Tests
• Liver (drug effects, metabolism)
• Male
• Nitric Oxide (metabolism)
• Organ Size
• Rats
• Receptors, Cytoplasmic and Nuclear (agonists)
• Sodium Chloride, Dietary