In an attempt to define novel genetic loci involved in the pathophysiology of primary aldosteronism a mutagenesis screen after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. One of the established mouse lines with hyperaldosteronism was phenotypically and genetically characterized. Affected animals showed an increased aldosterone to renin ratio (males unaffected, 1.1±0.1 pg/ml per ng per ml per hour versus affected, 3.9±0.8 pg/ml per ng per ml per hour, P<0.01, females unaffected, 1.8±0.2 pg/ml per ng per ml per hour versus affected, 4.4±0.7 pg/ml per ng per ml per hour, P<0.01), normal potassium, urea and creatinine, and an increase of blood pressure only in female animals (systolic BP unaffected 124±3 vs 118±3 mmHg, P<0.05). Furthermore, immunohistochemistry revealed increased collagen deposits in hearts of affected animals. Surprisingly, however, while gross adrenal morphology was similar between the groups, lower adrenal Cyp11b2 expression levels were evident in affected littermates (males, 37±8% and females, 25±8% versus unaffected, 100%), whereas StAR and P450scc expression showed no significant differences. In addition aldosterone release from adrenals kept in organ culture was significantly lower in affected animals (males affected 21±5 ng/ml versus unaffected 45±4 ng/ml, P<0.005 and females affected 82±12 ng/ml versus unaffected 122±9 ng/ml, P<0.05). As lack of Cyp11b2 expression in a variety of tissues did not support extra-adrenal aldosterone secretion, ongoing functional characterization aims at the elucidation of mechanisms involved in the observed elevation of aldosterone levels. A SNP analysis revealed significant linkage (χ2 of 9.94) with chromosome 9, locus 80.06. Further microsatellite and heteroduplex analyses by TGCE technique are in process for fine mapping and eventually identification of the mutation causative for the described phenotype.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology