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A mutant mouse (tx) with increased hepatic metallothionein stability and accumulation.

ABSTRACT: Metallothioneins (MTs) are low-molecular-mass cysteine-rich proteins implicated in metal homoeostasis and resistance to toxicity induced by heavy metals and alkylating agents. We report high hepatic MT protein accumulation (greater than 100-fold compared with wild-type mice) in toxic milk (tx) mice, along with markedly higher cytosol copper and zinc levels. Increased MT-gene transcription alone could not account for the high constitutive MT protein levels, since MT mRNA levels were not increased in tx mouse livers. However, hepatic MT was significantly more stable in adult tx mice: MT half-life (t1/2) was 79 or 77% greater than in wild-type mice before and after Cd induction respectively. Cd or Zn treatment increased MT mRNA, but not MT protein, accumulation in tx mouse livers: Cd displaced MT-bound Zn and Cu in preexisting MT. Thus tx mice appear to accumulate hepatic MT as a result of decreased protein degradation. These animals may provide a useful model to study the physiological role of MT, and human diseases (such as Wilson's disease) with abnormal copper metabolism.

SUBMITTER: Koropatnick J

PROVIDER: S-EPMC1137715 | biostudies-other | 1993 Dec

REPOSITORIES: biostudies-other

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Project description:Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid-refractory acute rejection. Eighty-three kidney transplant recipients (1995-2005), who were treated with methylprednisolone during a first acute rejection episode, were included in this study. Gene expression patterns were investigated in a discovery cohort of 36 acute rejection biopsies, and verified in a validation cohort of 47 acute rejection biopsies. In the discovery set, expression of metallothioneins (MT) was significantly (P<0.000001) associated with decreased response to steroid treatment. Multivariate analysis resulted in a predictive model containing MT-1 as an independent covariate (AUC=0.88, P<0.0000001). In the validation set, MT-1 expression was also significantly associated with steroid resistance (P=0.029). Metallothionein expression was detected in macrophages and tubular epithelial cells. Parallel to the findings in patients, in vitro experiments of peripheral blood mononuclear cells from 11 donors showed that non-response to methylprednisolone treatment is related to highly elevated MT levels. High expression of metallothioneins in renal allografts is associated with resistance to steroid treatment. Metallothioneins regulate intracellular concentrations of zinc, through which they may diminish the zinc-requiring anti-inflammatory effect of the glucocorticoid receptor. Transcriptional profiles of 40 renal allograft biopsy samples were analyzed using Illumina HumanRef-8 v3.0 BeadChips (Illumina, San Diego, CA). Expression profiles were investigated in total RNA isolated from biopsy samples of 18 patients with steroid responsive acute rejection and 18 patients with steroid resistant acute rejection. Four biopsies, taken during acute decrease of graft function but with no histomorphologic indication of rejection, were included as controls.

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A mutant mouse (tx) with increased hepatic metallothionein stability and accumulation.

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