Loss of A1 Adenosine Receptor Attenuates Alpha-naphthylisothiocyanate-Induced Cholestatic Liver Injury in Mice

Abstract

Cholestasis has limited therapeutic options and is associated with high morbidity and mortality. The A(1) adenosine receptor (A(1)AR) was postulated to participate in the pathogenesis of hepatic fibrosis induced by experimental extrahepatic cholestasis; however, the contribution of A(1)AR to intrahepatic cholestatic liver injury remains unknown. Here, we found that mice lacking A(1)AR were resistant to alpha-naphthyl isothiocyanate (ANIT)-induced liver injury, as evidenced by lower serum liver enzyme levels and reduced extent of histological necrosis. Bile acid accumulation in liver and serum was markedly diminished in A(1)AR(-/-) mice compared with wild-type (WT) mice. However, biliary and urinary outputs of bile acids were significantly enhanced in A(1)AR(-/-) mice. In the liver, mRNA expression of genes related to bile acid transport (Bsep and Mdr2) and hydroxylation (Cyp3a11) was increased in A(1)AR(-/-) mice. In the kidney, A(1)AR deficiency prevented the decrease of glomerular filtration rate caused by ANIT. Treatment of WT mice with A(1)AR antagonist DPCPX also protected against ANIT hepatotoxicity. Our results indicated that lack of A(1)AR gene protects mice from ANIT-induced cholestasis by enhancing toxic biliary constituents efflux through biliary excretory route and renal elimination system and suggested a potential role of A(1)AR as therapeutic target for the treatment of intrahepatic cholestasis.

Danning tablets attenuates α-naphthylisothiocyanate-induced cholestasis by modulating the expression of transporters and metabolic enzymes

“…In contrast, renal mRNA level of Asbt was significantly down-regulated, accompanied by increased concentrations of bile acid and bilirubin in urine. These results indicated that adaptive responses to cholestasis also occur in the kidney in an effort to eliminate excess bile acids and toxic compounds from circulation which is according with previous report [29]. In addition, DNts pretreatment further increased the renal mRNA level of Ostβ in ANIT-intoxicated rats, accompanied by further increase in urinary excretion of bile acid and bilirubin (Figure  7).…”

PER1 prevents excessive innate immune response during endotoxin-induced liver injury through regulation of macrophage recruitment in mice

“…Proteins were extracted following the procedure described previously. 50 The proteins were separated by SDS-PAGE on 8–12% polyacrylamide gels and subsequently electrically transferred to a PVDF membrane. After blocking with 5% (w/v) BSA in TBST at room temperature for 1 h, the membranes were then incubated with an appropriate specific primary antibody (anti-HA, 1 : 2000; anti-PPAR- γ , 1 : 1000; anti-PER1, 1 : 200; anti- β -actin, 1 : 1000) at 4 °C overnight, followed by incubation with an HRP-conjugated secondary antibody (1 : 10 000).…”

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“…The receptor that seems to be mainly responsible for adenosine protection is A 2b AR 47, 48 . A 1 AR was also shown to have a protective effect against ethanol-induced hepatotoxicity 49 and to protect against alpha-naphthylisothiocyanate-induced cholestatic liver injury induced by DPCPX (a specific A 1 AR antagonist) in A 1 AR deficient mice 50 . A 2a AR is expressed by heptatic stellate cells, where it regulates fibrogenesis and contractility 51, 52 .…”