Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy.
BACKGROUND
We report the induction of gremlin, a bone morphogenetic protein antagonist, in cultured human mesangial cells exposed to high glucose and transforming growth factor beta (TGF-beta) levels in vitro and kidneys from diabetic rats in vivo.


METHODS
Gremlin expression was assessed in human diabetic nephropathy by means of in situ hybridization, immunohistochemistry, and real-time polymerase chain reaction and correlated with clinical and pathological indices of disease.


RESULTS
Gremlin was not expressed in normal human adult kidneys. Conversely, abundant gremlin expression was observed in human diabetic nephropathy. Although some gremlin expression was observed in occasional glomeruli, gremlin expression was most prominent in areas of tubulointerstitial fibrosis, where it colocalized with TGF-beta expression. Gremlin messenger RNA levels correlated directly with renal dysfunction, determined by means of serum creatinine level, but not with proteinuria level. There was a strong correlation between gremlin expression and tubulointerstitial fibrosis score.


CONCLUSIONS
In aggregate, these results indicate that the developmental gene gremlin reemerges in the context of tubulointerstitial fibrosis in diabetic nephropathy and suggests a role for TFG-beta as an inducer of gremlin expression in this context.
Dolan
Vincent
V
Department of Medicine, The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Mater Misericordiae University Hospital, Dublin, Ireland. vincent.dolan@ucd.ie
Murphy
Madeline
M
Sadlier
Denise
D
Lappin
David
D
Doran
Peter
P
Godson
Catherine
C
Martin
Finian
F
O'Meara
Yvonne
Y
Schmid
Holger
H
Henger
Anna
A
Kretzler
Matthias
M
Droguett
Alejandra
A
Mezzano
Sergio
S
Brady
Hugh R
HR
D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007680:Kidney Neoplasms / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000378:metabolism; D011506:Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D019485:Bone Morphogenetic Proteins; D016207:Cytokines; C486399:GREM1 protein, human; C107276:Grem1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D005947:Glucose