Inactivation of extrahepatic vascular Akt improves systemic hemodynamics and sodium excretion in cirrhotic rats.
OBJECTIVE
Increased activity of the vascular Akt/eNOS signaling pathway is involved in the hemodynamic and renal complications developed by patients and rats with cirrhosis and ascites. This occurs in the setting of impaired Akt/eNOS activity within the cirrhotic liver. Here we assessed the feasibility of selectively inhibiting vascular eNOS without further impairing the intrahepatic activity of this enzyme. Ultimately, we sought to determine whether endothelial transduction of a constitutively inactive mutant of Akt (AA-Akt) improves circulatory function and sodium excretion in cirrhotic rats with ascites.


METHODS
First, we administered recombinant adenoviruses that encode the β-galactosidase gene (β-gal) to 5 control rats and 5 cirrhotic rats with ascites and analyzed their tissue distribution by chemiluminescence. Next, urine samples were obtained from 18 cirrhotic rats with ascites and then the animal randomly received saline or adenoviruses containing the β-gal or the AA-Akt genes. Following a 24-h urine collection period, hemodynamic studies were performed and tissue samples were obtained to analyze Akt and eNOS expressions.


RESULTS
No β-gal activity was detected in the liver of cirrhotic rats compared to that of controls. This was paralleled by increased β-gal activity in other territories such as the thoracic aorta. AA-Akt transduction improved systemic hemodynamics, splanchnic perfusion pressure and renal excretory function in comparison with cirrhotic rats transduced with β-gal adenoviruses or receiving saline. Moreover, the AA-Akt transgene did not modify portal pressure.


CONCLUSIONS
Inactivation of extrahepatic vascular Akt and the concomitant decrease in nitric oxide expression ameliorate systemic hemodynamics and renal excretory function in experimental cirrhosis.
Fernández-Varo
G
G
Biochemistry and Molecular Genetics Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
Melgar-Lesmes
P
P
Casals
G
G
Pauta
M
M
Arroyo
V
V
Morales-Ruiz
M
M
Ros
J
J
Jiménez
W
W
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001201:Ascites / Q000209:etiology / Q000503:physiopathology; D002417:Cattle; D002478:Cells, Cultured; D057809:HEK293 Cells; D006439:Hemodynamics; D006801:Humans; D008102:Liver Circulation; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology* / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D050505:Mutant Proteins / Q000235:genetics; D009318:Natriuresis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics; D014161:Transduction, Genetic
D050505:Mutant Proteins; D011994:Recombinant Proteins; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt