Endocrine Abstracts (2004) 7 P225

Gene expression responses induced in kidney by aldosterone excess and salt

E Marshall1, P Dickenson2, T Forster2, D Roy2, CJ Kenyon1 & RW Brown1


1Endocrinology Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK; 2Scottish Centre for Genomic Technology and Informatics, The University of Edinburgh, Edinburgh, UK.


Renal sodium handling and responses to aldosterone (aldo) are conserved across species and intrinsic to the dominant role of the kidney in long-term blood pressure (BP) control. Molecular pathways involved in hypertensive responses to aldo and escape from these remain largely unclear despite identification of several participant genes. We have characterized renal gene expression changes in mice, receiving aldo and/or dietary salt excess, using microarray analysis and concurrent physiological observations. Component treatments which in combination induce hypertension (modified DOCA-salt model) were thus examinable separately.

Adult male C57BL/6 mice having food and fluid intake and BP monitoring were given group(n=6) treatments of:- (1) control - normal, 0.3% Na+, feed, saline-only s.c. mini-pump (MP); (2)aldo excess - 150microg aldosterone/kg/day by MP, 0.3% Na+ feed; (3)high salt - 3% Na+ diet, saline-only MP; (4)aldo+salt - 150microg/kg/day, 3% Na+ diet. After 6 days treatment kidneys were taken for analysis and plasma renin activity and aldosterone allowed confirmation of adequacy of treatments. Cy-3 probes generated from total kidney RNA samples of mice were hybridised(n=3/group) to mouse known gene chips(HGMP, MRC, UK) having 7542 oligo sets arrayed in duplicate. Hybridization results were processed by ScanArray 4000 and QuantArray software systems. Permutation t-tests identified significant (p<0.01) expression changes c.f. controls with:- 188 higher, 74 lower with aldo excess; 122 higher, 151 lower with high salt and 88 higher, 92 lower with aldo+salt. Key expected changes were manifest e.g. lower renin expression with aldo excess and group expression changes in genes involved in oxidative phosphorylation. Genes involved in responses to glomerular stress and tissue injury were upregulated by aldo excess plus/minus high salt. These and other novel findings elucidate prohypertensive pathways active in aldosterone and salt excess and suggest molecular routes to accompanying renal damage

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