Hormones – Cytokines – Signalling
Kidney International (2003) 64, 1199–1207; doi:10.1046/j.1523-1755.2003.00216.x
Early aldosterone up-regulated genes: New pathways for renal disease?
Markus Kellner, Angela Peiter, Mathias Hafner, Martin Feuring, Michael Christ, Martin Wehling, Elisabeth Falkenstein and Ralf Lösel
Institute of Clinical Pharmacology, Faculty of Clinical Medicine at Mannheim, University of Heidelberg, Germany; Department of Molecular Biology and Cell Culture Technology, Mannheim University of Applied Sciences, Mannheim, Germany; and Department of Internal Medicine-Cardiology, Phillips-University of Marburg, Marburg, Germany
Correspondence: Prof Dr med. Martin Wehling, Institute of Clinical Pharmacology, Universitätsklinikum Mannheim, Universität Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany. E-mail: martin.wehling@kpha.ma.uni-heidelberg.de
Received 25 September 2002; Revised 31 March 2003; Accepted 23 May 2003.
Abstract
Early aldosterone up-regulated genes: New pathways for renal disease?
Background
The use of aldosterone antagonists has important beneficial effects on the progression of renal and cardiac disease reflected in a decrease of cardiovascular mortality and renal failure. Nevertheless, the incidence of heart and end-stage renal failure continues to increase. This leads to the conclusion that mechanisms independent of the classical aldosterone/mineralocorticoid receptor system may contribute to the pathogenesis of cardiac and renal disease.
Methods
The mRNA expression profile of human renal epithelial cells in response to aldosterone was characterized using cDNA arrays covering 
1430 genes. Differentially expressed genes were further evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR), Northern blotting, and estimating the gene products by Western blotting.
Results
Aldosterone treatment of cells resulted in significant up-regulation of several genes within 1 hour, with sgk, p21/waf1, gadd45, and gadd153 being the most significant ones. Long-term treatment (>4 hours) with aldosterone induced the mRNA expression of ppar
and pur. The mineralocorticoid receptor inhibitor spironolactone decreased the mRNA levels of sgk, p21/waf1, and gadd45, whereas the glucocorticoid receptor inhibitor RU 486 reduced the mRNA level of sgk and p21/waf1. Gadd153 was not affected by any of the inhibitors, probably indicating regulation by nonclassic mechanisms.
Conclusion
Among the early genes investigated in this study, one transcript has been identified that is not suppressed by antagonists of either glucocorticoid or mineralocorticoid receptor. Further studies should be able to identify other genes regulated in a similar manner that could explain the inefficacy of spironolactone in some cases of aldosterone-mediated kidney disease.
Keywords:
aldosterone, gene regulation, kidney, spironolactone, nonclassic receptors, renal disease
