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

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          Epithelial sodium channel regulated by aldosterone-induced protein sgk.

          Sodium homeostasis in terrestrial and freshwater vertebrates is controlled by the corticosteroid hormones, principally aldosterone, which stimulate electrogenic Na+ absorption in tight epithelia. Although aldosterone is known to increase apical membrane Na+ permeability in target cells through changes in gene transcription, the mechanistic basis of this effect remains poorly understood. The predominant early effect of aldosterone is to increase the activity of the epithelial sodium channel (ENaC), although ENaC mRNA and protein levels do not change initially. Rather, the open probability and/or number of channels in the apical membrane are greatly increased by unknown modulators. To identify hormone-stimulated gene products that modulate ENaC activity, a subtracted cDNA library was generated from A6 cells, a stable cell line of renal distal nephron origin, and the effect of candidates on ENaC activity was tested in a coexpression assay. We report here the identification of sgk (serum and glucocorticoid-regulated kinase), a member of the serine-threonine kinase family, as an aldosterone-induced regulator of ENaC activity. sgk mRNA and protein were strongly and rapidly hormone stimulated both in A6 cells and in rat kidney. Furthermore, sgk stimulated ENaC activity approximately 7-fold when they were coexpressed in Xenopus laevis oocytes. These data suggest that sgk plays a central role in aldosterone regulation of Na+ absorption and thus in the control of extracellular fluid volume, blood pressure, and sodium homeostasis.
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            Molecular Mechanisms of Myocardial Remodeling

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              Gene regulation of connective tissue growth factor: new targets for antifibrotic therapy?

              Connective tissue growth factor (CTGF) has recently received much attention as a possible key determinant of progressive fibrosis and excessive scarring and also of wound repair, neoangiogenesis, bone formation and embryonic development. CTGF is also up regulated in numerous fibrotic diseases, including atherosclerosis and lung-, skin-, pancreas-, liver- and kidney-fibrosis. TGFbeta induces CTGF through different signaling pathways and a specific TGFbeta responsive element in the CTGF promoter. CTGF is thought to act both as a profibrotic marker and as a downstream effector of TGFbeta by mediating at least some of its profibrotic activities. CTGF is an interesting target for future antifibrotic therapies as it is conceivable that inhibition of CTGF might block the profibrotic effects of TGFbeta, without affecting TGFbeta's anti-proliferative and immunosuppressive effects. In addition to TGFbeta, a number of other regulators of CTGF expression have been identified, including vascular endothelial growth factor, tumor necrosis factor alpha, shear stress, cell stretch and static pressure, H(2)O(2), O(2) and NO. In addition to trans-regulatory mechanisms, specific transcription factor binding sites in the CTGF promoter, as well as 3'untranslated region (UTR) regulatory sequences have been identified that are important for basal and induced CTGF expression. Outlining the mechanisms that underlie CTGF gene regulation in normal and fibrotic cells, might help design of future intervention strategies aiming at targeted specific interference with CTGF expression at sites of progressive fibrosis. In addition, alternative therapies targeting CTGF effects are proposed which might lead to a favorable outcome of wound repair and fibrosis. Copyright 2002 Elsevier Science B.V. and International Society of Matrix Biology
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                Author and article information

                Journal
                Journal of Molecular Medicine
                J Mol Med
                Springer Science and Business Media LLC
                0946-2716
                1432-1440
                September 2006
                August 10 2006
                September 2006
                : 84
                : 9
                : 737-746
                Article
                10.1007/s00109-006-0082-0
                f0285af8-d9e1-412f-a5e4-3eb292bc90dc
                © 2006

                http://www.springer.com/tdm

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