Apelin is a
peptide that plays an important role in heart physiology and pathophysiology,
inflammation, and angiogenesis. We evaluated whether the endogenous
apelin system is involved in the pathogenesis of the hepatic remodeling and cardiovascular and renal complications occurring in advanced
liver disease. The circulating levels of
apelin, the
messenger RNA (
mRNA) and
protein expression of
apelin and
apelin receptor, the immunohistological detection of
apelin and
apelin receptor, and the effects induced by the chronic administration of an
apelin receptor antagonist on
fibrosis and vessel density were evaluated in rats with
cirrhosis and
ascites and in control rats. The serum levels of
apelin in patients with
cirrhosis were also measured.
Apelin levels were higher in rats with
cirrhosis than in controls.
Apelin mRNA showed a four-fold rise only in hepatic tissue, but not in the lung, heart, or kidney of rats with
cirrhosis. These animals also showed hepatic
apelin receptor mRNA levels 300 times higher than controls.
Apelin was highly expressed by stellate cells, whereas
apelin receptor was overexpressed in the hepatic parenchyma of animals with
cirrhosis. Rats with
cirrhosis treated with the
apelin receptor antagonist showed diminished hepatic
fibrosis and vessel density, improved cardiovascular performance, and renal function and lost
ascites. Human patients also showed a marked increase in
apelin levels.
CONCLUSION: The selective hepatic activation of the
apelin system, together with the drop in
fibrosis and neoangiogenesis and the improvement in cardiovascular and excretory function resulting from
apelin receptor blockade, points to the hepatic
apelin system as a novel therapeutic target in
liver disease.