No abstract

Glucocorticoid hormones, acting via nuclear receptors, regulate many metabolic processes, including hepatic gluconeogenesis. It recently has been recognized that intracellular glucocorticoid concentrations are determined not only by plasma hormone levels, but also by intracellular 11␤-hydroxysteroid dehydrogenases (11␤-HSDs), which interconvert active corticosterone (cortisol in humans) and inert 11-dehydrocorticosterone (cortisone in humans). 11␤-HSD type 2, a dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data suggest the type 1 isozyme (11␤-HSD-1) may function as an 11␤-reductase, regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. To examine the importance of this enzyme isoform in vivo, mice were produced with targeted disruption of the 11␤-HSD-1 gene. These mice were unable to convert inert 11-dehydrocorticosterone to corticosterone in vivo. Despite compensatory adrenal hyperplasia and increased adrenal secretion of corticosterone, on starvation homozygous mutants had attenuated activation of the key hepatic gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, presumably, because of relative intrahepatic glucocorticoid deficiency. The 11␤-HSD-1 ؊͞؊ mice were found to resist hyperglycamia provoked by obesity or stress. Attenuation of hepatic 11␤-HSD-1 may provide a novel approach to the regulation of gluconeogenesis.

SummaryFollowing liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired, a feature of human chronic liver disease1,2. It is contested whether other liver cell types can regenerate hepatocytes3–5. Here, we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. Firstly, loss of β1-Integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, and ~25% of hepatocytes being derived from a non-hepatocyte origin. Secondly cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-Integrin knockdown or p21 over-expression, resulting in the significant emergence of cholangiocyte derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.

A novel inbred rat model with inducible hypertension has been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1 promoter. The degree and duration of hypertension are regulated tightly by administration of the natural xenobiotic indole-3 carbinol and can be readily reversed. Induction experiments reveal distinct temporal and mechanistic responses to hypertensive injury in different vascular beds, which is indicative of differential susceptibility of organs to a hypertensive stimulus. The mesentery and heart exhibited the greatest sensitivity to damage, and the kidney showed an adaptive response prior to the development of malignant hypertensive injury. Quantitative analysis of morphological changes induced in mesenteric resistance arteries suggest eutrophic remodeling of the vessels. Kinetic evidence suggests that locally activated plasma prorenin may play a critical role in mediating vascular injury. This model will facilitate studies of the cellular and genetic mechanisms underlying vascular injury and repair and provide a basis for the identification of novel therapeutic targets for vascular disease.Essential hypertension has a complex multifactorial phenotype. Both genetic and environmental factors influence its development, and understanding the pathogenesis of complications such as vascular lesions and end-organ damage may lead to more specific treatment and targeted intervention.We have identified candidate loci in rats that may contribute to target organ damage and mortality in malignant hypertension (MH), 1 a condition characterized by an accelerated rise in blood pressure, endothelial injury, activation of the reninangiotensin system, and microangiopathy (1). Several animal models have been generated to investigate the pathophysiology of hypertensive vascular injury. Most animal models of MH to date require surgical or pharmacological intervention to precipitate onset or depend on the constitutive expression of endogenous genes or heterologous transgenes (2-5). In rats doubly transgenic for human renin and angiotensinogen genes, hypertension and fibrinoid vasculitis (5) accompanied by alteration in surface adhesion molecules, proinflammatory cytokines, fibrogenic mediators and leukocyte infiltration (6) have been reported. In most of these models, the onset of disease cannot be determined precisely.The initiation events of pathological processes can only be studied in an animal model in which hypertension is induced by tightly temporally regulated gene expression. If the onset and level of hypertension can be controlled, then the cellular and molecular events during initiation of the vascular and organ injury can be identified unequivocally. Reversibility of the gene expression provides an opportunity to study the molecular and cellular basis of repair. We therefore have generated inbred transgenic rats with inducible hypertension using the cytochrome P450 promoter, Cyp1a1, to drive expression of the mouse Ren-2 gene. The transgene is expressed primarily ...