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SGK1-dependent cardiac CTGF formation and fibrosis following DOCA treatment

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Abstract

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 μM) 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-κB (NFκB). Our results suggest that SGK1 plays a decisive role in mineralocorticoid-induced CTGF expression and cardiac fibrosis.

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Acknowledgements

This work was supported by grants from DFG (SFB/TR 19-04), the Department of Veterans Affairs, the National Institutes of Health (DK56248, DK28602), and BMBF (D.K., F.L., V.V., A.G., K.K., R.K.). The support of Drs. M. Bonin, Genetics Department, and A. Mack, Anatomy Department of the University of Tübingen, are acknowledged. There are no potential conflicts of interest anywhere, relating to this article.

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Authors and Affiliations

  1. Departments of Pharmacology & Toxicology, University of Tübingen, Tübingen, Germany

    Volker Vallon, Dan Yang Huang & Hartmut Osswald

  2. Departments of Medicine & Pharmacology, University of California San Diego & VASDHCS, CA, USA

    Volker Vallon, Nancy D. Dalton & John Ross Jr

  3. Department of Physiology, University of Tübingen, Tubingen, Germany

    Amanda W. Wyatt, Azeemudeen Hussain, Susanne Berchtold, Florian Grahammer & Florian Lang

  4. Department of Molecular Pathology, University of Tübingen, Tübingen, Germany

    Karin Klingel & Reinhard Kandolf

  5. Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany

    Björn Friedrich

  6. Department of Pediatric Cardiology, German Heart Center, Munich, Germany

    Rachida S. BelAiba & Agnes Görlach

  7. Department of Clinical Neurobiology, University Hospital Heidelberg, Heidelberg, Germany

    Peer Wulff

  8. Department of Physiology, University of Marburg, Marburg, Germany

    Jürgen Daut

  9. Department of Cardiovascular Physiology, University of Düsseldorf, Düsseldorf, Germany

    Ulrich Flögel & Jürgen Schrader

  10. Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany

    Dietmar Kuhl

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  1. Volker Vallon
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Correspondence to Florian Lang.

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V. Vallon and A.W. Wyatt contributed equally to this work.

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Vallon, V., Wyatt, A.W., Klingel, K. et al. SGK1-dependent cardiac CTGF formation and fibrosis following DOCA treatment. J Mol Med 84, 396–404 (2006). https://doi.org/10.1007/s00109-005-0027-z

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