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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Are Angiotensin II Receptor Antagonists Useful Strategies in Steatotic and Nonsteatotic Livers in Conditions of Partial Hepatectomy under Ischemia-Reperfusion?

Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain (F.S.R., J.R.-C.); Unitat de Transplantament de Fetge i Viabilitat de l'Empelt, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Consejo Superior de Investigaciones Científicas, Barcelona, Spain (I.A.-F., A.C.-R., M.M.-S., J.R.-C., C.P.); Centro de Investigaciones Biomédicas Esther Koplowitz, Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain (I.A.-F., A.C.-R, M.M.-S., A.R., V.A., J.R., J.R.-C., C.P.); Centre de Biotecnologia Animal i Terapia Genica, Universitat Autónoma de Barcelona, Barcelona, Spain (A.S.); and Liver Unit, Hospital Clinic Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain (A.R., V.A., J.R.)

We examined whether angiotensin (Ang) II receptor antagonists could be considered a therapeutic strategy in steatotic and nonsteatotic livers in conditions of partial hepatectomy under ischemia-reperfusion (I/R), which is commonly applied in clinical practice to reduce blood loss. We report that Ang II type I receptor (AT1R) antagonist, but not Ang II type II receptor (AT2R) antagonist, increased regeneration in nonsteatotic livers. In the presence of steatosis, both AT1R and AT2R antagonists increased liver regeneration. This effect was stronger when the two were combined. Neither of the Ang II receptor antagonists protected nonsteatotic livers against damage. Only the AT1R antagonist, through nitric oxide inhibition, reduced damage in steatotic livers. The combination of the AT1R and AT2R antagonists in steatotic livers conferred a similar degree of protection to AT1R antagonist alone. Herein, we show that p38 mitogen-activated protein kinase (p38) was a key mechanism in the regeneration induced by the Ang II receptor antagonists in both liver types because when this signaling pathway was inhibited, the beneficial effects of the Ang II receptor antagonists on liver regeneration disappeared, regardless of hepatocyte growth factor or transforming growth factor β-hepatic levels. In conclusion, in conditions of partial hepatectomy under I/R, the AT1R antagonist for nonsteatotic livers and the AT1R and AT2R antagonists for steatotic livers improved regeneration in the remnant liver through p38 activation. In addition, the combination of the AT1R and AT2R antagonists in steatotic livers led to stronger liver regeneration than either antagonists used separately and also provided the same protection against damage as that afforded by AT1R antagonist alone.

Address correspondence to: Dr. Joan Roselló-Catafau, Institut d'Investigacions Biomèdiques August Pi i Sunyer-Consejo Superior de Investigaciones Cientificas, C/Roselló 161, 7th floor, 08036 Barcelona, Spain. E-mail: jrcbam{at}iibb.csic.es