Gremlin: a novel mediator of epithelial mesenchymal transition and fibrosis in chronic allograft nephropathy.
BACKGROUND
Chronic allograft nephropathy (CAN) is the most frequent cause of chronic dysfunction and late loss of renal allografts. Epithelial mesenchymal transition (EMT) has been identified as responsible for the presence of activated interstitial fibroblasts (myofibroblasts) and transforming growth factor beta (TGF-beta)/Smad is the key signaling mediator. It has been proposed that the bone morphogenetic protein 7 (BMP-7) antagonist, Gremlin, could participate in EMT, as a downstream mediator of TGF-beta.


METHODS
We evaluated 33 renal allograft biopsies, 16 of which showed CAN, versus 17 controls. By in situ hybridization we studied the expression of TGF-beta and Gremlin mRNA. Gremlin, BMP-7, E-cadherin, and alpha-smooth muscle actin (alpha-SMA) proteins were evaluated by immunohistochemistry and Smad3 activation by Southwestern. In cultured human tubuloepithelial cells (HK2 cell line), Gremlin induction by TGF-beta was studied by confocal microscopy.


RESULTS
Among renal biopsies of transplanted patients with CAN, we detected up-regulation of TGF-beta in colocalization with Gremlin (RNA and protein), mainly in areas of tubulointerstitial fibrosis. In the same tubules, we observed decreased expression of E-cadherin and induction of vimentin and alpha-SMA. BMP-7 was significantly decreased in the CAN biopsies. In addition, HK2 stimulated with TGF-beta (1 ng/mL) induced Gremlin production at 72 hours.


CONCLUSIONS
We postulated that Gremlin is a downstream mediator of TGF-beta, suggesting a role for Gremlin in EMT observed in CAN.
Carvajal
G
G
Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile.
Droguett
A
A
Burgos
M E
ME
Aros
C
C
Ardiles
L
L
Flores
C
C
Carpio
D
D
Ruiz-Ortega
M
M
Egido
J
J
Mezzano
S
S
D002454:Cell Differentiation; D002908:Chronic Disease; D004847:Epithelial Cells / Q000473:pathology*; D005355:Fibrosis; D006801:Humans; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D016030:Kidney Transplantation / Q000473:pathology*; D008648:Mesoderm / Q000473:pathology*; D011183:Postoperative Complications / Q000473:pathology*; D014184:Transplantation, Homologous
C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins