IHG-1 amplifies TGF-beta1 signaling and is increased in renal fibrosis.
Induced in high glucose-1 (IHG-1) is an evolutionarily conserved gene transcript upregulated by high extracellular glucose concentrations, but its function is unknown. Here, it is reported that the abundance of IHG-1 mRNA is nearly 10-fold higher in microdissected, tubule-rich renal biopsies from patients with diabetic nephropathy compared with control subjects. In the diabetic nephropathy specimens, in situ hybridization localized IHG-1 to tubular epithelial cells along with TGF-beta1 and activated Smad3, suggesting a possible role in the development of tubulointerstitial fibrosis. Supporting this possibility, IHG-1 mRNA and protein expression also increased with unilateral ureteral obstruction. In the HK-2 proximal tubule cell line, overexpression of IHG-1 increased TGF-beta1-stimulated expression of connective tissue growth factor and fibronectin. IHG-1 was found to amplify TGF-beta1-mediated transcriptional activity by increasing and prolonging phosphorylation of Smad3. Conversely, inhibition of endogenous IHG-1 with small interference RNA suppressed transcriptional responses to TGF-beta1. In summary, IHG-1, which increases in diabetic nephropathy, may enhance the actions of TGF-beta1 and contribute to the development of tubulointerstitial fibrosis.
Murphy
Madeline
M
UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. madeline.murphy@ucd.ie
Docherty
Neil G
NG
Griffin
Brenda
B
Howlin
Jillian
J
McArdle
Emmett
E
McMahon
Ruth
R
Schmid
Holger
H
Kretzler
Matthias
M
Droguett
Alejandra
A
Mezzano
Sergio
S
Brady
Hugh R
HR
Furlong
Fiona
F
Godson
Catherine
C
Martin
Finian
F
D000595:Amino Acid Sequence; D002460:Cell Line; D055513:Connective Tissue Growth Factor; D017124:Conserved Sequence; D003928:Diabetic Nephropathies / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D005947:Glucose / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000378:metabolism*
C526317:CCN2 protein, human; D005353:Fibronectins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C532028:THG1L protein, human; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D005947:Glucose