Stimulation of serum- and glucocorticoid-regulated kinase-1 gene expression by endothelin-1.
The serum- and glucocorticoid-regulated kinase-1 (SGK1) participates in the regulation of sodium homeostasis and blood pressure by mineralocorticoids. Aldosterone rapidly induces SGK1 transcription, which contributes to the activation of renal epithelial sodium channels. Another important regulator of blood pressure is the vasoactive hormone endothelin-1 (ET-1) that is systemically upregulated in chronic renal failure. In the present study, we investigated whether ET-1 modulates SGK1 expression, and thereby might explain some of its hypertensive effects. As assessed by real-time PCR analysis, ET-1 triggered the rapid increase of SGK1 mRNA levels in A-10 smooth muscle cells and also in intact aortas of adult rats. In A-10 cells transcriptional activation was associated with a more than 6-fold upregulation of SGK1 protein expression and in similar range as found after treatment with aldosterone. A stimulatory effect of ET-1 was not only observed in isolated cells, but also in an animal model. Upon subtotal nephrectomy (SNX) of rats, myocardial ET-1 levels strongly increased, which was followed by a more than 2-fold induction of SGK1 expression in the left ventricle. The myocardial upregulation of SGK1 was completely abrogated by a specific ET(A) receptor antagonist, thereby substantiating the in vivo role of ET-1 in SGK1 expression. Thus, these data demonstrate that ET-1 increases expression of SGK1 in vivo and in vitro, and therefore indicate that SGK1 upregulation might be involved in ET-1-dependent regulation of blood pressure and cardiac modelling during mild renal failure.
Medical Clinic IV, Section of Nephrology, Hypertension and Renal Failure, University of Tübingen, Germany.
Sabine C
SC
Wolf
Michael
M
Schultze
Teut
T
Risler
Timo
T
Rieg
Florian
F
Lang
Klaus
K
Schulze-Osthoff
Bernhard R
BR
Brehm
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000494:pharmacology; D002460:Cell Line; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics*; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology; D009206:Myocardium / Q000378:metabolism; D009392:Nephrectomy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D001559:Benzhydryl Compounds; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D012333:RNA, Messenger; D000099184:Serum-Glucocorticoid Regulated Kinases; C405519:BSF 302146