title: Early aldosterone up-regulated genes: new pathways for renal disease?
abstract: 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 approximately 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 pparalpha and puralpha. 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Clinical Pharmacology, Faculty of Clinical Medicine at Mannheim, University of Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kellner
authors.forename: Angela
authors.initials: A
authors.lastname: Peiter
authors.forename: Mathias
authors.initials: M
authors.lastname: Hafner
authors.forename: Martin
authors.initials: M
authors.lastname: Feuring
authors.forename: Michael
authors.initials: M
authors.lastname: Christ
authors.forename: Martin
authors.initials: M
authors.lastname: Wehling
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Falkenstein
authors.forename: Ralf
authors.initials: R
authors.lastname: Lösel
mesh_terms: D000450:Aldosterone / Q000494:pharmacology / Q000502:physiology*; D015152:Blotting, Northern; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D020869:Gene Expression Profiling; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007674:Kidney Diseases / Q000235:genetics; D015735:Mifepristone / Q000494:pharmacology; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000494:pharmacology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology*; D000097642:GADD45 Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D022762:CCAAT-Enhancer-Binding Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006727:Hormone Antagonists; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015735:Mifepristone; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D013148:Spironolactone; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000097642:GADD45 Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C493956:CDKN1A protein, human; C497249:DDIT3 protein, human