PKB/SGK-resistant GSK-3 signaling following unilateral ureteral obstruction

Jakob Voelkl, Sobuj Mia, Adrian Meissner, Mohamed S. Ahmed, Martina Feger, Bernat Elvira, Britta Walker, Dario R. Alessi, Ioana Alesutan, Florian Lang

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    21 Citations (Scopus)
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    Abstract

    Background/Aims: Renal tissue fibrosis contributes to the development of end-stage renal disease. Causes for renal tissue fibrosis include obstructive nephropathy. The development of renal fibrosis following unilateral ureteral obstruction (UUO) is blunted in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1. Similar to Akt isoforms, SGK1 phosphorylates and thus inactivates glycogen synthase kinase GSK-3. The present study explored whether PKB/SGK-dependent phoshorylation of GSK-3/β impacts on pro-fibrotic signaling following UUO.

    Methods: UUO was induced in mice carrying a PKB/SGK-resistant GSK-3/β (gsk-3KI) and corresponding wild-type mice (gsk-3WT). Three days after the obstructive injury, expression of fibrosis markers in kidney tissues was analyzed by quantitative RT-PCR and western blotting.

    Results: GSK-3 and GSK-3β phosphorylation was absent in both, the non-obstructed and the obstructed kidney tissues from gsk-3KI mice but was increased by UUO in kidney tissues from gsk-3WT mice. Expression of -smooth muscle actin, type I collagen and type III collagen in the non-obstructed kidney tissues was not significantly different between gsk-3KI mice and gsk-3WT mice but was significantly less increased in the obstructed kidney tissues from gsk-3 KI mice than from gsk-3WT mice. After UUO treatment, renal β-catenin protein abundance and renal expression of the β-catenin sensitive genes: c-Myc, Dkk1, Twist and Lef1 were again significantly less increased in kidney tissues from gsk-3KI mice than from gsk-3 WT mice.

    Conclusions: PKB/SGK-dependent phosphorylation of glycogen synthase kinase GSK-3 contributes to the pro-fibrotic signaling leading to renal tissue fibrosis in obstructive nephropathy.

    Original languageEnglish
    Pages (from-to)156-164
    Number of pages9
    JournalKidney and Blood Pressure Research
    Volume38
    Issue number1
    Early online date15 Mar 2014
    DOIs
    Publication statusPublished - Mar 2014

    Keywords

    • Glycogen synthase kinase 3
    • Protein kinase B
    • Renal fibrosis
    • Serum- and glucocorticoid-inducible kinase
    • Unilateral ureteral obstruction
    • Wnt
    • β-catenin

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