SGK1-dependent cardiac CTGF formation and fibrosis following DOCA treatment.
The mineralocorticoids aldosterone and deoxycorticosterone acetate (DOCA) stimulate renal tubular salt reabsorption, increase salt appetite, induce extracellular volume expansion, and elevate blood pressure. Cardiac effects of mineralocorticoids include stimulation of matrix protein deposition leading to cardiac fibrosis, which is at least partially due to the direct action of the hormones on cardiac cells. The signaling mechanisms mediating mineralocorticoid-induced cardiac fibrosis have so far remained elusive. Mineralocorticoids have been shown to upregulate the serum- and glucocorticoid-inducible kinase 1 (SGK1), which participates in the effects of mineralocorticoids on renal tubular Na+ reabsorption and salt appetite. To explore the involvement of SGK1 in the pathogenesis of mineralocorticoid-induced cardiac fibrosis, SGK1 knockout mice (sgk1-/-) and wild-type littermates (sgk1+/+) were implanted a 21-day-release 50-mg DOCA pellet and supplied with 1% NaCl in drinking water for 18 days. This DOCA/high-salt treatment increased blood pressure in both genotypes but led to significant cardiac fibrosis only in sgk1+/+ but not in sgk1-/- mice. According to real-time polymerase chain reaction and Western blotting, DOCA/high-salt treatment enhanced transcript levels and protein expression of cardiac connective tissue growth factor (CTGF) only in sgk1+/+ but not in sgk1-/- mice. Furthermore, DOCA (10 microM) upregulated CTGF expression and enhanced CTGF promoter activity in lung fibroblasts isolated from sgk1+/+ but not from sgk1-/- mice, an effect involving spironolactone-sensitive mineralocorticoid receptors and activation of nuclear factor-kappaB (NFkappaB). Our results suggest that SGK1 plays a decisive role in mineralocorticoid-induced CTGF expression and cardiac fibrosis.
Vallon
Volker
V
Department of Pharmacology & Toxicology, University of Tübingen, Tübingen, Germany.
Wyatt
Amanda W
AW
Klingel
Karin
K
Huang
Dan Yang
DY
Hussain
Azeemudeen
A
Berchtold
Susanne
S
Friedrich
Björn
B
Grahammer
Florian
F
Belaiba
Rachida S
RS
Görlach
Agnes
A
Wulff
Peer
P
Daut
Jürgen
J
Dalton
Nancy D
ND
Ross
John
J
Flögel
Ulrich
U
Schrader
Jürgen
J
Osswald
Hartmut
H
Kandolf
Reinhard
R
Kuhl
Dietmar
D
Lang
Florian
F
D000809:Angiotensins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D055513:Connective Tissue Growth Factor; D003900:Desoxycorticosterone / Q000009:adverse effects / Q000031:analogs & derivatives*; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D000451:Mineralocorticoid Receptor Antagonists; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012492:Salts / Q000494:pharmacology; D013148:Spironolactone / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases
D000809:Angiotensins; D055513:Connective Tissue Growth Factor; D003900:Desoxycorticosterone; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000451:Mineralocorticoid Receptor Antagonists; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D012492:Salts; D013148:Spironolactone; D000099184:Serum-Glucocorticoid Regulated Kinases; C526318:CCN2 protein, mouse