Background: Hepatorenal syndrome (HRS) is a life-threatening complication of advanced liver cirrhosis that is characterized by hemodynamic alterations in the kidney and other vascular beds. Cytochrome P(CYP)-450 enzymes metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acids. These eicosanoids regulate blood pressure, vascular tone and renal tubular sodium transport under both physiological and pathophysiological states. Methods: Experiments were performed to investigate the role of the CYP system in the pathogenesis of renal dysfunction during cirrhosis. Rats underwent bile duct ligation (BDL) or sham surgery and were studied at 2, 4 and 5 weeks post-surgery. In additional experiments, post-BDL rats were treated with three daily intraperitoneal doses of either the selective epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH) or a vehicle, starting on Day 22 after surgery. Results: BDL led to progressive renal dysfunction that was associated with reduced renal cortical perfusion but without any overt histologic changes, consistent with HRS. CYP isoform enzyme expression was significantly altered in BDL rats. In the kidney, CYP2C23 expression was upregulated at both the mRNA and protein levels in BDL rats, while CYP2C11 was downregulated. Histologically, the changes in CYP2C23 and CYP2C11 expression were localized to the renal tubules. EET production was increased in the kidneys of BDL rats as assessed by urinary eicosanoid levels. Finally, treatment with the selective epoxygenase inhibitor MSPPOH significantly reduced renal function and renal cortical perfusion in BDL rats, suggesting a homeostatic role for epoxygenase-derived eicosanoids. Conclusions: The CYP/EET pathway might represent a novel therapeutic target for modulating renal dysfunction in advanced cirrhosis.
Background: Hepatorenal syndrome (HRS) is a life-threatening complication of advanced liver cirrhosis that is characterized by hemodynamic alterations in the kidney and other vascular beds. Cytochrome P(CYP)-450 enzymes metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acids. These eicosanoids regulate blood pressure, vascular tone and renal tubular sodium transport under both physiological and pathophysiological states. Methods: Experiments were performed to investigate the role of the CYP system in the pathogenesis of renal dysfunction during cirrhosis. Rats underwent bile duct ligation (BDL) or sham surgery and were studied at 2, 4 and 5 weeks post-surgery. In additional experiments, post-BDL rats were treated with three daily intraperitoneal doses of either the selective epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH) or a vehicle, starting on Day 22 after surgery. Results: BDL led to progressive renal dysfunction that was associated with reduced renal cortical perfusion but without any overt histologic changes, consistent with HRS. CYP isoform enzyme expression was significantly altered in BDL rats. In the kidney, CYP2C23 expression was upregulated at both the mRNA and protein levels in BDL rats, while CYP2C11 was downregulated. Histologically, the changes in CYP2C23 and CYP2C11 expression were localized to the renal tubules. EET production was increased in the kidneys of BDL rats as assessed by urinary eicosanoid levels. Finally, treatment with the selective epoxygenase inhibitor MSPPOH significantly reduced renal function and renal cortical perfusion in BDL rats, suggesting a homeostatic role for epoxygenase-derived eicosanoids. Conclusions: The CYP/EET pathway might represent a novel therapeutic target for modulating renal dysfunction in advanced cirrhosis.
Authors: Paolo Angeli; Pere Gines; Florence Wong; Mauro Bernardi; Thomas D Boyer; Alexander Gerbes; Richard Moreau; Rajiv Jalan; Shiv K Sarin; Salvatore Piano; Kevin Moore; Samuel S Lee; Francois Durand; Francesco Salerno; Paolo Caraceni; W Ray Kim; Vicente Arroyo; Guadalupe Garcia-Tsao Journal: Gut Date: 2015-01-28 Impact factor: 23.059
Authors: Joan Clària; Rudolf E Stauber; Minneke J Coenraad; Richard Moreau; Rajiv Jalan; Marco Pavesi; Àlex Amorós; Esther Titos; José Alcaraz-Quiles; Karl Oettl; Manuel Morales-Ruiz; Paolo Angeli; Marco Domenicali; Carlo Alessandria; Alexander Gerbes; Julia Wendon; Frederik Nevens; Jonel Trebicka; Wim Laleman; Faouzi Saliba; Tania M Welzel; Agustin Albillos; Thierry Gustot; Daniel Benten; François Durand; Pere Ginès; Mauro Bernardi; Vicente Arroyo Journal: Hepatology Date: 2016-08-25 Impact factor: 17.425
Authors: Andrew S Allegretti; Xavier Vela Parada; Guillermo A Ortiz; Joshua Long; Scott Krinsky; Sophia Zhao; Bryan C Fuchs; Mozhdeh Sojoodi; Dongsheng Zhang; S Ananth Karumanchi; Sahir Kalim; Sagar U Nigwekar; Ravi I Thadhani; Samir M Parikh; Raymond T Chung Journal: Hepatology Date: 2019-01-04 Impact factor: 17.425
Authors: Andrew S Allegretti; Xavier Vela Parada; Paul Endres; Sophia Zhao; Scott Krinsky; Shelsea A St Hillien; Sahir Kalim; Sagar U Nigwekar; James G Flood; Andrea Nixon; Douglas A Simonetto; Luis A Juncos; Nithin Karakala; Hani M Wadei; Kevin R Regner; Justin M Belcher; Mitra K Nadim; Guadalupe Garcia-Tsao; Juan Carlos Q Velez; Samir M Parikh; Raymond T Chung Journal: Clin Transl Gastroenterol Date: 2021-05-11 Impact factor: 4.396