Endocrine Abstracts (2008) 16 P28

Establishment of a mutagenesis screen to identify mice with high aldosterone levels

Ariadni Spyroglou1, Sibylle Wagner2, Jenny Manolopoulou1, Constanze Hantel1, Martin Reincke1, Martin Bidlingmaier1, Martin Hrabé de Angelis2 & Felix Beuschlein1

1Medizinische Klinik Innenstadt, Ludwig-Maximilians-University, Munich, Germany; 2Institute of Experimental Genetics, GSF-National Research Centre for Environment and Health, Munich, Germany.

According to recent studies, primary aldosteronism is considered to be responsible for almost 10% of all cases of arterial hypertension. The genetic background of this common disease, however, has been elucidated only for the rare familial types whereas in the large majority of sporadic cases it still remains unclear. In an attempt to define novel genetic mechanisms of hyperaldosteronism we utilized a random mutagenesis screen after treatment with the alkylating agent N-ethylnitrosourea (ENU) and phenotypically characterized affected mice for their plasma aldosterone levels. As the detection method we used a time resolved fluorescence immunoassay, which allows the measurement of aldosterone in very small murine sample volumes. Using this assay we determined the normal aldosterone values for C3HeB/FeJ wild type mice under baseline conditions (mean±S.D.; 92±53 pg/ml for females (n=69) and 173±114 pg/ml for males (n=55)) and following specific stimulation and suppression tests. Subsequently, aldosterone measurement was carried out in more than 2000 male and female F1 offspring of chemically mutated inbred C3HeB/FeJ mice. Upon repeated measurement, 7 female animals of the tested F1 offspring had consistently elevated aldosterone levels (defined as 3 S.D.’s above the mean of untreated animals) measured at a mean of 456±104 pg/ml at initial time point. So far, no affected male mice have been detected. Further breeding of affected female animals gave rise to F2 pedigrees from which one established line displays high aldosterone values in 50% of littermates as would be expected from an autosomal dominant trait of inheritance. These animals will serve for detailed phenotypic and genetic characterization in the future. Taken together our data demonstrate the feasibility of a phenotype-driven mutagenesis screen to detect and establish mutant mouse lines with a high aldosterone phenotype.

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