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Blunted DOCA/high salt induced albuminuria and renal tubulointerstitial damage in gene-targeted mice lacking SGK1

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Abstract

Mineralocorticoids stimulate renal tubular Na+ reabsorption, enhance salt appetite, increase blood pressure, and favor the development of renal fibrosis. The effects of mineralocorticoids on renal tubular Na+ reabsorption and salt appetite involve the serum- and glucocorticoid-inducible kinase 1 (SGK1). The kinase is highly expressed in fibrosing tissue. The present experiments thus explored the involvement of SGK1 in renal fibrosis. To this end, SGK1-knockout mice (sgk1 −/−) and their wild-type littermates (sgk1 +/+) were implanted with desoxycorticosterone acetate (DOCA)-release pellets and offered 1% saline as drinking water for 12 weeks. The treatment led to significant increases in fluid and Na+ intake and urinary output of fluid and Na+ in sgk1 +/+ mice, effects blunted in sgk1 −/− mice. Blood pressure increased within the first 7 weeks to a similar extent in both genotypes, but within the next 5 weeks, it increased further only in sgk1 +/+ mice. Creatinine clearance did not change significantly but albuminuria increased dramatically in sgk1 +/+ mice, an effect significantly blunted in sgk1 −/− mice. Histology after 12 weeks treatment revealed marked glomerular sclerosis and tubulointerstitial damage with interstitial fibrosis and inflammation in kidneys from sgk1 +/+ mice, but not from sgk1 −/− mice. In conclusion, a lack of SGK1 protects against DOCA/high-salt-induced albuminuria and renal fibrosis.

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Acknowledgements

This work was supported by grants from Deutsche Forschungsgemeinschaft, La 315/4-6, Sonderforschungsbereich 423 (project Z2), the Department of Veterans Affairs, and the National Institutes of Health (DK56248, DK28602). O. Nasir was a recipient of a Deutscher Akademischer Austauschdienst fellowship.

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Authors and Affiliations

  1. Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany

    Ferruh Artunc, Omaima Nasir, Diana Sandulache, Nermina Jahovic & Florian Lang

  2. Department of Internal Medicine IV, University of Tübingen, Otfried-Müller-Str 10, 72076, Tübingen, Germany

    Björn Friedrich & Teut Risler

  3. Department of Pathology, University of Erlangen, Erlangen, Germany

    Kerstin Amann

  4. Departments of Medicine and Pharmacology, University of California San Diego and VASDHCS, San Diego, CA, USA

    Volker Vallon

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

    Peer Wulff

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

    Dietmar Kuhl

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  1. Ferruh Artunc
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Artunc, F., Amann, K., Nasir, O. et al. Blunted DOCA/high salt induced albuminuria and renal tubulointerstitial damage in gene-targeted mice lacking SGK1. J Mol Med 84, 737–746 (2006). https://doi.org/10.1007/s00109-006-0082-0

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