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Spyroglou, A.* ; Wagner, S.* ; Manolopoulou, J.* ; Hantel, C.* ; Reincke, M.* ; Bidlingmaier, M.* ; Hrabě de Angelis, M. ; Beuschlein, F.*

Characterisation of a mouse model with mutagenesis induced hyperaldosteronism.

Vortrag: 11th European Congress of Endocrinology, 25-29 April 2009, Istanbul, Turkey. (2009)
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Although primary aldosteronism (PA) is considered to be the most prevalent cause of secondary hypertension the underlying genetic mechanisms have been elucidated only for the rare familial forms of the disease. In an attempt to define novel genetic loci involved in the pathophysiology of PA a phenotype-driven mutagenesis screening after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. The aldosterone values of more than 2800 F1 offspring of chemically mutated inbred C3HeB/FeJ mice were measured and compared to aldosterone levels from untreated animals. Persistent hyperaldosteronism (defined as levels +3 SD over the mean of untreated animals) upon repeated measurements was present in 8 female and 1 male F1 offspring. Further breeding of these affected female animals gave rise to F2 pedigrees from which eight lines with different patterns of inheritance of hyperaldosteronism could be established. Affected animals served for a detailed phenotypic characterization which revealed low renin values, an increased aldosterone to renin ratio (unaffected: 1.83±0.54 pg/ml/ng/ml/hr vs. affected: 5.9±1.63 pg/ml/ng/ml/hr, P<0.01) and low potassium (unaffected: 5.44±0.05 mmol/l vs. affected: 4.78±0.23 mmol/l, P<0.05) in line with the presence of primary aldosteronism. In addition, the investigation of their cardiac phenotype showed increased collagen deposits and subsequently cardiac fibrosis (picric acid positive areas unaffected: 0.63±0.02% vs. affected: 2.00±0.14%, P<0.01). Histological examination of their adrenal glands revealed a thicker zona glomerulosa (zona glomerulosa/zona fasciculata ratio unaffected: 0.23±0.01 vs. affected: 0.39±0.02, P<0.001) without evidence of adrenal tumors. On the molecular level affected animals showed a significant increase of Cyp11b2 expression (unaffected: 100±8% vs. affected: 649±76%, P<0.001) which was accompanied by a significant downregulation of the genes Smoc, MTUS and Wnt4 in comparison to unaffected littermates. Ongoing SNP analysis will allow defining causative mutations to elucidate the molecular mechanisms of autonomous aldosterone secretion in the individual lines.
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Publikationstyp Sonstiges: Vortrag
Konferenztitel 11th European Congress of Endocrinology
Konferzenzdatum 25-29 April 2009
Konferenzort Istanbul, Turkey