Growth arrest specific protein 6 participates in DOCA-induced target-organ damage.
Growth arrest-specific protein 6 (Gas 6) is involved in inflammatory kidney diseases, vascular remodeling, cell adhesion, and thrombus formation. We explored a role for Gas 6 in aldosterone-induced target organ damage. We observed that Gas 6 was upregulated in rats with high aldosterone levels. Mineralocorticoid receptor blockade prevented target organ damage and decreased the elevated Gas 6 expression. Vascular smooth muscle cells given aldosterone increased their Gas 6 expression in vitro. To test the pathophysiological relevance, we investigated the effects of deoxycorticosterone acetate (DOCA) on Gas 6 gene-deleted ((-/-)) mice. After 6 weeks DOCA, Gas 6(-/-) mice developed similar telemetric blood pressure elevations compared to wild-type mice but were protected from cardiac hypertrophy. Cardiac expression of interleukin 6 and collagen IV was blunted in Gas 6(-/-) mice, indicating reduced inflammation and fibrosis. Gas 6(-/-) mice also had an improved renal function with reduced albuminuria, compared to wild-type mice. Renal fibrosis and fibronectin deposition in the kidney were also reduced. Gas 6 deficiency reduces the detrimental effects of aldosterone on cardiac and renal remodeling independent of blood pressure reduction. Gas 6 appears to play a role in mineralocorticoid receptor-mediated target organ damage. Furthermore, because warfarin interferes with Gas 6 protein expression, the findings could be of clinical relevance for anticoagulant choices.
Park
Joon-Keun
JK
Robert-Rössle-Str 10, 13125 Berlin, Germany.
Theuer
Stefanie
S
Kirsch
Torsten
T
Lindschau
Carsten
C
Klinge
Uwe
U
Heuser
Arnd
A
Plehm
Ralph
R
Todiras
Mihai
M
Carmeliet
Peter
P
Haller
Hermann
H
Luft
Friedrich C
FC
Muller
Dominik N
DN
Fiebeler
Anette
A
D058186:Acute Kidney Injury / Q000473:pathology / Q000503:physiopathology*; D000419:Albuminuria; D000450:Aldosterone / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D003900:Desoxycorticosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D000099255:Growth Arrest-Specific Protein 6
D000450:Aldosterone; D003900:Desoxycorticosterone; D036341:Intercellular Signaling Peptides and Proteins; D000099255:Growth Arrest-Specific Protein 6