Adenosine Administration Accelerates Progression of the Cell Cycle during Rat Liver Regeneration Induced by One-Third Hepatectomy

Abstract

We have shown that adenosine administration is capable of reversing fibrosis in the carbon tetrachloride-induced rat cirrhotic liver, stimulating the diminished proliferative potential of the cirrhotic liver. To characterize adenosine actions on liver cellular proliferation, we used rats subjected to one-third partial hepatectomy (PH). In PH animals acutely administered with adenosine (25-200 mg/kg b.w.), parameters indicative of cell proliferation were determined. In addition, hepatocyte growth factor (HGF), epidermal growth factor, and transforming growth factor-␣, cyclins, members of the E2F family, proto-oncogenes, and adenosine-receptors were determined through Western blot analyses. Adenosine (100 mg/kg body weight) induced an earlier increase in liver cell proliferation as evidenced by enhanced levels of proliferating cell nuclear antigen, nuclear Ki-67 antigen, and those for cyclins (D1, E, A, and B1), as well as by an increased mitotic index. These effects were also accompanied for a long-lasting increase of serum and liver levels of HGF and liver expression of c-Met and HGF liver activator. Adenosine effects on cell proliferation could be mediated by an early increase in E2F-1 and by that of c-Myc, despite the fact that phosphorylation of the Rb protein and expression of E2F-3 were decreased. Moreover, the liver amount of specific receptors for adenosine was not significantly changed by PH and/or adenosine treatment. In conclusion, these data suggest that adenosine actions can accelerate and increase proliferation in a "primed" liver, mainly through enhancing c-Myc, E2F family, cell-cycle cyclins, and HGF expression. Therefore, these pharmacological adenosine effects suggest a modulating role for the nucleoside on mitogenic events once the liver has been triggered to proliferate.Liver regeneration represents proliferation of highly differentiated cells in order to rapidly reconstitute the original functional mass of the organ even after 70% partial hepatectomy (PH) in rats. During regeneration, liver functions are compromised and limited to the minimum, depending on an equilibrium between the essential functions and the rate of cell proliferation tightly controlled in the remnant liver (Michalopoulos and DeFrances, 1997).The PH has been a useful model to study liver regeneration for many years, given an ordered and synchronized proliferation of hepatic cells and involving various phases of the cell cycle (Michalopoulos and DeFrances, 1997). In rats subjected to PH, it is possible to establish different thresholds of proliferation, proportional to the extent of the removed liver mass. Indeed, one-third PH produces a low proliferative burst, with diverse metabolic changes that differ from the maximum achieved with two-thirds PH (Herná ndez-Muñ oz et López-Valencia et al., 2007), proving useful to assess effects of drugs with presumably stimulatory or inhibitory actions on cell proliferation.We reported previously that adenosine administration (200 mg/kg b.w., administered intraperitoneally three ...

Transcription factors ETF, E2F, and SP-1 are involved in cytokine-independent proliferation of murine hepatocytes

“…Concerning the second model, PHx, we could show by an in silico approach that the differential gene expression induced by PHx is also characterized by an overrepresentation of TFBS for the same TFs—ETF, E2F, and SP‐1—indicating that such cytokine‐independent events contribute to the initiation of proliferation under conditions where the integrity of parenchyma remains intact. Recent work34 showing that nuclear E2F1 increases in rat hepatocytes after one‐third PHx corroborates the importance of this TF, independent of the species studied.…”

Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

“…In initial experiments, we analyzed expression of PCNA, a nuclear protein that is up-regulated in proliferating cells (Mendieta-Condado et al , 2009). In wild type mice acetaminophen caused in a time dependent increase in PCNA staining in hepatocyte nuclei in periportal regions of the liver, which was evident within 3 h and remained elevated for at least 96 h (Fig.…”

Recovery of the Cell Cycle Inhibition inCCl4-Induced Cirrhosis by the Adenosine Derivative IFC-305

“…In fact, in this study we found that the overexpression of the A2a receptor protein during cirrhosis decreases in the presence of IFC-305 (Figure 7), suggesting a role of this receptor in the described effect. Previously, we showed that the inhibitory effect of IFC305 in hepatic stellate cells activation was not mediated by adenosine receptors, but it was related with adenosine transport and intracellular AMP formation [42], neither in the adenosine acceleration of the cell cycle after one-third hepatectomy [19]. Possibly, a diminution of A2a receptor expression induced by the IFC305 increases adenosine transport into the cell promoting their effects in DNA repair and maintaining the energetic equilibrium.…”

“…In preestablished cirrhosis, adenosine increases collagen degradation, prevents its accumulation, preserves the energy and functional states of the liver, increases DNA synthesis, the mitotic index, and the expression of proliferating cell nuclear antigen (PCNA) [7]. Recently, we have demonstrated that adenosine administration accelerates progression of the cell cycle during liver regeneration in rats subjected to one-third hepatectomy [19]. Some of these effects, such as prevention of collagen accumulation and increase in DNA synthesis, have been reproduced with the IFC-305 [5, 10].…”