Hypothalamic vasopressin release and hepatocyte Ca ²⁺ signaling during liver regeneration: an interplay stimulating liver growth and bile flow

Abstract

Liver regeneration after partial hepatectomy is a plastic process during which the mechanisms that coordinate liver mass restoration compensate one another through a complex regulatory network of cytokines, growth factors, and hormones. Vasopressin, an agonist that triggers highly organized Ca2+ signals in the liver, may be one of these factors, although little in vivo evidence is available in support of this hypothesis. We provide evidence that hypothalamic vasopressin secretion is stimulated early after partial hepatectomy. Although hepatocytes were fully responsive to vasopressin during the first hours of regeneration, they became desensitized and exhibited slow oscillating Ca2+ responses to vasopressin on the following days. On the first day, hepatocyte V1a receptor density decreased and its lobular gradient increased in hepatectomized rats. By antagonizing the V1a receptor in vivo, we demonstrated that vasopressin contributes to NF-kappaB and cyclin (D1 and A) activation, to hepatocyte progression in the cell cycle, and to liver mass restoration. Finally, vasopressin exerted a choleretic effect shortly after hepatectomy, both in the isolated perfused liver and in the intact rat. In conclusion, we provide compelling in vivo evidence that vasopressin contributes significantly to growth initiation and bile flow stimulation in the early stages of liver regeneration.

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

“…Liver regeneration after partial hepatectomy was significantly inhibited in Brattleboro rats that were deficient of AVP (434) or rats treated with the V1a antagonist (372). Administration of AVP into Brattleboro rats after partial hepatectomy increased hepatic DNA and protein synthesis and restored hepatic regeneration (434), supporting the idea that AVP controls liver cell proliferation and growth in vivo as well as in vitro.…”

“…When we investigated the functional role of the V1a receptor in regulating hepatocyte proliferation and growth using V1aR-KO and WT mice, a number of V1aR-KO mice died within 24 h after a two-thirds hepatectomy (Tanoue, unpublished data), whereas most WT mice survived a partial hepatectomy and their livers were completely restored to their initial mass within a few days, as observed in control rats (372,434). Among the biochemical markers studied in mice, blood ammonia levels were significantly higher in V1aR-KO mice than those in WT controls, but most other parameters, including AST and ALT, in V1aR-KO mice were indistinguishable from WT mice (219).…”

“…AVP is reported to promote not only cell proliferation and growth but also organ regeneration (372,508). Liver regeneration after partial hepatectomy was significantly inhibited in Brattleboro rats that were deficient of AVP (434) or rats treated with the V1a antagonist (372).…”

“…Administration of AVP into Brattleboro rats after partial hepatectomy increased hepatic DNA and protein synthesis and restored hepatic regeneration (434), supporting the idea that AVP controls liver cell proliferation and growth in vivo as well as in vitro. During liver regeneration, AVP stimulates the progression of the cell cycle of the hepatocytes by activation of NF-B and cyclin (D1 and A), which contributes to liver mass restoration in rats (372). In sheep livers, however, the V1a receptor is absent.…”

Mice Lacking bi-1 Gene Show Accelerated Liver Regeneration

“…2+ concentrations occur during cell cycle entry in hepatocytes during liver regeneration (33)(34)(35). Of relevance to cell proliferation, this increase in intracellular Ca 2+ has been correlated with activation of the calmodulin-dependent phosphatase calcineurin (36,37).…”