dinoprost and Hepatorenal-Syndrome

Topics: Animals; Diabetes Mellitus; Dinoprost; F2-Isoprostanes; Hepatorenal Syndrome; Humans; Vasoconstrictor Agents

The present study explores the potential of chronic treatment with the Foresaid X receptor (FXR) agonist obeticholic acid (OCA), which inhibits oxidative stress-related pathogenesis, in ascitic cirrhotic rats with hepatorenal syndrome (HRS) developed 6 weeks after bile duct ligation (BDL).. Systemic, splanchnic, and renal hemodynamics and pathogenic cascades were measured in ascitic BDL and sham rats receiving 2-weeks of either vehicle or OCA treatments (sham-OCA and BDL-OCA groups), and NRK-52E cells, rat kidney tubular epithelial cells.. Chronic OCA treatment significantly normalized portal hypertension, glomerular filtration rate, urine output, renal blood flow; decreased ascites, renal vascular resistance, serum creatinine, and the release of renal tubular damage markers, including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury moleculae-1 (uKim-1) in BDL-OCA rats. In the BDL group, inhibition of the renal oxidative stress (8-iso-PGF2α)-activated cyclooxygenase-thromboxane A2 [COX-TXA2] pathway, apoptosis, and tubular injury accompanied by a decrease in hyper-responsiveness to the vasoconstrictor 8-iso-PGF2α in perfused kidneys. In vitro experiments revealed that 8-iso-PGF2α induced oxidative stress, release of reactive oxygen species, and cell apoptosis, which were reversed by concomitant incubation with the FXR agonist.. Through the inhibition of renal 8-iso-PGF2α production and the down-regulation of the COX-TXA2 pathway, our study suggests that chronic OCA treatment can ameliorate the HRS in ascitic cirrhotic rats. Thus, OCA is an agent with antioxidative stress, antivasoconstrictive, antiapoptotic properties which benefit ascitic, cirrhotic rats with systemic, hepatic, and renal abnormalities.

Topics: Animals; Apoptosis; Cell Line; Chenodeoxycholic Acid; Dinoprost; Drug Evaluation, Preclinical; Glutathione; Hepatorenal Syndrome; Liver Cirrhosis; Male; Oxidative Stress; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Thiobarbituric Acid Reactive Substances; Thromboxane A2; Vascular Resistance; Vasoconstriction

To assess the role of altered renal and systemic production of thromboxane A2 and prostacyclin in the hepatorenal syndrome, urinary excretion of their major renal and extrarenal metabolites was measured in patients with compensated and decompensated liver disease, chronic renal failure, and hepatorenal syndrome. Urinary excretion rates of all prostanoids (renal and extrarenal) were increased in subjects with liver disease compared with normal controls. Moreover, they were considerably higher in subjects with severe hepatic decompensation but good renal function compared with those with hepatorenal syndrome. In contrast, the excretion rate of all metabolites was reduced in patients with chronic renal failure. The excretion rate of all metabolites was markedly elevated during the early stages of hepatorenal syndrome and decreased in parallel with creatinine clearance. When corrected for creatinine clearance, there was a strong correlation between prostanoid excretion and serum bilirubin in subjects with liver disease; there was no difference, however, in the excretion of renal and extrarenal prostanoids between hepatorenal syndrome and severe hepatic decompensation. It is concluded that hepatic decompensation is associated with a progressive increase in prostanoid excretion but that changes in production of prostacyclin or thromboxane A2 are unlikely to be major factors in the pathogenesis of the hepatorenal syndrome.

Topics: Adult; Aged; Ascites; Bilirubin; Creatinine; Dinoprost; Epoprostenol; Female; Hepatorenal Syndrome; Humans; Kidney; Kidney Failure, Chronic; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Thromboxane A2; Thromboxane B2