Growth arrest specific protein 6 participates in DOCA-induced target-organ damage.

Abstract

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.

• Authors: Joon-Keun Park, Stefanie Theuer, Torsten Kirsch, Carsten Lindschau, Uwe Klinge, Arnd Heuser, Ralph Plehm, Mihai Todiras, Peter Carmeliet, Hermann Haller, Friedrich C Luft, Dominik N Muller, Anette Fiebeler
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 54 Issue 2 Pg. 359-64 (Aug 2009) ISSN: 1524-4563 [Electronic] United States
• PMID: 19564549 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intercellular Signaling Peptides and Proteins
• growth arrest-specific protein 6
• Desoxycorticosterone
• Aldosterone

Topics

• Acute Kidney Injury (pathology, physiopathology)
• Albuminuria
• Aldosterone (pharmacology)
• Analysis of Variance
• Animals
• Blood Pressure (drug effects)
• Cardiomegaly (pathology, physiopathology)
• Cells, Cultured (cytology, drug effects)
• Desoxycorticosterone (pharmacology)
• Disease Models, Animal
• Gene Expression Regulation
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Kidney (drug effects, pathology)
• Mice
• Mice, Knockout
• Muscle, Smooth, Vascular (cytology)
• Probability
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Species Specificity