Toward nitric oxide deficiency in hepatorenal syndrome: Is farnesoid X receptor the link?

Hepatorenal syndrome (HRS) is a major complication of cholestatic liver disease (CLD), characterized by vasoconstriction. Since nitric oxide (NO) is a potent vasodilator, NO deficiency has been proposed to cause HRS. Retention of bile acid plays a role in liver damage; however, whether bile acid triggers extrahepatic tissue damage is unclear. Farnesoid X receptor (FXR) is a bile acid-sensor nuclear receptor abundant in the kidney. We recently found increased oxidative stress and asymmetric dimethylarginine (ADMA) are major causes of NO deficiency. We hypothesize that impaired regulation of FXR and its target genes by bile acid within the kidney resulting in HRS through two major mechanisms: First, increased oxidative stress due to decreased glutathione/reduced glutathione ratio, which is regulated by FXR-target genes, multidrug resistance-associated proteins (MRPs); Second, increased ADMA due to impaired regulation of protein arginine methyltransferase (PRMT, ADMA-synthesizing enzyme) 1 and dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme) by FXR. Therefore, FXR agonist may be a therapeutic approach to treat HRS via reducing oxidative stress and ADMA to restore NO in CLD.