Increased epoxyeicosatrienoic acid formation in the rat kidney during liver cirrhosis. J Am Soc Nephrol 2003 Jul;14(7):1766-75
Date
06/24/2003Pubmed ID
12819236DOI
10.1097/01.asn.0000076074.63334.99Scopus ID
2-s2.0-0037530612 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
Vascular complications during liver cirrhosis are often severe, particularly in the kidney. These complications are the result of complex and poorly understood interactions between the injured liver and other organs such as the lungs, heart, and kidney. The purpose of this study was to investigate the alterations to renal hemodynamics during cirrhosis, focusing on the actions of epoxyeicosatrienoic acids (EET), known to be potent regulators of renal hemodynamics. Cirrhosis was induced in rats by common bile duct ligation (CBDL), and they were compared with sham rats. Experiments were conducted 4 wk after either the sham or CBDL surgery. Vasoreactivity was assessed in isolated perfused kidneys. cPLA(2) expression and cytochrome P450 (CYP450) expression were measured using Western blot. cPLA(2) enzymatic activity was measured by radioenzymatic assay. EET production was measured using rpHPLC analysis. The major findings were that kidneys from CBDL rats had significantly greater acetylcholine-induced vasodilation that was partially blocked by nitric oxide (NO) and prostaglandin inhibition and fully blocked by the combined inhibition of NO, prostaglandins, and CYP450 metabolites. Expression and activity of cPLA(2) in CBDL kidneys was increased, providing arachidonic acid substrate to the CYP450 enzymes. Finally, expression and activity of CYP450 enzymes was elevated in CBDL kidneys, resulting in significantly greater production of the vasodilating 11,12-EET and 14,15-EET. While it is well documented that renal vasoconstriction leading to impaired renal function occurs during cirrhosis, our data clearly demonstrate that endogenous production of EET is increased in cirrhotic kidneys. This may be a homeostatic response to preserve renal perfusion.
Author List
Miyazono M, Zhu D, Nemenoff R, Jacobs ER, Carter EPMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAcetylcholine
Animals
Arachidonic Acid
Bile Ducts
Blotting, Western
Body Weight
Cell Division
Chromatography, High Pressure Liquid
Cytochrome P-450 Enzyme System
Dose-Response Relationship, Drug
Hemodynamics
Kidney
Liver Cirrhosis
Nitric Oxide
Perfusion
Phospholipases A
Protein Isoforms
Rats
Time Factors
