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(Hypertension. 2009;54:359.)
© 2009 American Heart Association, Inc.

Original Articles

Growth Arrest Specific Protein 6 Participates in DOCA-Induced Target-Organ Damage

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

From the Department of Internal Medicine-Nephrology (J.-K.P., T.K., C.L., H.H., A.F.), Hannover University Medical School, Germany; the Experimental and Clinical Research Center (S.T., C.L., A.H., R.P., M.T., F.C.L., D.N.M., A.F.), Franz Volhard Clinic HELIOS Klinikum-Berlin and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Germany; University Hospital RWTH-Aachen and Helmholtz Institute (U.K.), Aachen, Germany; and the Versalius Research Center, VIB (P.C.) and the Versalius Research Center, K.U. (P.C.), Leuven, Belgium.

Correspondence to Anette Fiebeler, Robert-Rössle-Str 10, 13125 Berlin, Germany. E-mail fiebeler{at}charite.de

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.

Key Words: Gas 6 • aldosterone • cardiac hypertrophy • albuminuria • inflammation