Format

Send to

Choose Destination
Am J Med Sci. 2012 Nov;344(5):374-82. doi: 10.1097/MAJ.0b013e31824369c5.

Sustained Wnt/β-catenin signaling rescues high glucose induction of transforming growth factor-β1-mediated renal fibrosis.

Author information

1
Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi, Taiwan.

Abstract

INTRODUCTION:

Although diabetic nephropathy is attributable to transforming growth factor-β1 (TGF-β1) overproduction in glomer-ular mesangial cells, the biological role of Wnt/β-catenin signaling in controlling high glucose-induced TGF-β1 has not yet been elucidated.

METHODS:

This study found that sustained Wnt/β-catenin signaling was required to protect glomerular mesangial cells from high glucose induction of TGF-β1-mediated fibrosis using in vitro and in vivo diabetic models.

RESULTS:

High glucose down-regulated the Wnt signaling associated with increased TGF-β1 and fibronectin messenger RNA expression in glomerular mesangial cells. Restoring Wnt4, Wnt5a and cytosolic β-catenin levels by transfecting Wnt4, Wnt5a and stable β-catenin alleviated the stimulatory effect of high glucose on c-Jun mediated TGF-β1 fibrosis. Transfection of kinase-active glycogen synthase kinase-3β (GSK-3β) also abrogated high glucose promotion of nuclear c-Jun levels, TGF-β1 and fibronectin messenger RNA expression in mesangial cells. Pharmacological modulation of GSK-3ββ and ββ-catenin signaling by recombinant Wnt5a or GSK-3β inhibitor (BIO or LiCl) suppressed high glucose promotion of TGF-β1-mediated fibrosis. Exogenous BIO and SB216763 alleviated TGF-β1-mediated fibrogenic expression in the kidneys of diabetic rats. Immunohistochemistry showed that GSK-3β inhibitor significantly reversed the diabetic attenuation of TGF-β1 and c-Jun coinciding with fibronectin immunoreactivity within glomeruli. Immunofluorescence demonstrated that cells within the glomeruli restored β-catenin expression after BIO and SB216763 treatment in cells within diabetic glomeruli colocalized with fragmented nuclei by 4',6-diamidino-2-phenylindole staining.

CONCLUSIONS:

Sustained Wnt signaling reduced c-Jun-dependent TGF-β1-mediated fibronectin accumulation in mesangial cells. These findings suggest that modulation of Wnt signaling is a viable alternative strategy to rescue the TGF-β1-mediated fibrotic signaling pathway in diabetic renal injury.

PMID:
22270399
DOI:
10.1097/MAJ.0b013e31824369c5
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center