Early aldosterone-induced gene product regulates the epithelial sodium channel by deubiquitylation.
The mineralocorticoid hormone aldosterone controls sodium reabsorption and BP largely by regulating the cell-surface expression and function of the epithelial sodium channel (ENaC) in target kidney tubules. Part of the stimulatory effect of aldosterone on ENaC is mediated by the induction of serum- and glucocorticoid-regulated kinase 1 (Sgk1), a kinase that interferes with the ubiquitylation of ENaC by ubiquitin-protein ligase Nedd4-2. In vivo early aldosterone-regulated mRNA now has been identified in microselected mouse distal nephron by microarray. From 22 mRNA that displayed a two-fold or more change, 13 were downregulated and nine were upregulated. Besides Sgk1, the induced mRNA include Grem2 (protein related to DAN and cerebrus [PRDC]), activating transcription factor 3, cAMP responsive element modulator, and the ubiquitin-specific protease Usp2-45. The induction of this last enzyme isoform was verified in mouse distal nephron tubule at the protein level. With the use of Hek293 cells, Xenopus oocytes, and mpkCCD(c14) cells as expression systems, it was shown that Usp2-45 deubiquitylates ENaC and stimulates ENaC-mediated sodium transport, an effect that is not additive to that of Sgk1. A deubiquitylating enzyme that targets ENaC in vitro and thus may play a role in sodium transport regulation was identified within a series of new in vivo early aldosterone-regulated gene products.
Fakitsas
Panagiotis
P
Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Adam
Gabriele
G
Daidié
Dorothée
D
van Bemmelen
Miguel X
MX
Fouladkou
Fatemeh
F
Patrignani
Andrea
A
Wagner
Ulrich
U
Warth
Richard
R
Camargo
Simone M R
SM
Staub
Olivier
O
Verrey
François
F
D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D010450:Endopeptidases / Q000235:genetics / Q000502:physiology*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases
D053503:Epithelial Sodium Channels; D025801:Ubiquitin; D000450:Aldosterone; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C579224:Usp2 protein, mouse