Gremlin: A Novel Mediator of Epithelial Mesenchymal Transition and Fibrosis in Chronic Allograft Nephropathy

BackgroundChronic 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-β)/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-β.MethodsWe evaluated 33 renal allograft biopsies, 16 of which showed CAN, versus 17 controls. By in situ hybridization we studied the expression of TGF-β and Gremlin mRNA. Gremlin, BMP-7, E-cadherin, and α-smooth muscle actin (α-SMA) proteins were evaluated by immunohistochemistry and Smad3 activation by Southwestern. In cultured human tubuloepithelial cells (HK2 cell line), Gremlin induction by TGF-β was studied by confocal microscopy.ResultsAmong renal biopsies of transplanted patients with CAN, we detected up-regulation of TGF-β 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 α-SMA. BMP-7 was significantly decreased in the CAN biopsies. In addition, HK2 stimulated with TGF-β (1 ng/mL) induced Gremlin production at 72 hours.ConclusionWe postulated that Gremlin is a downstream mediator of TGF-β, suggesting a role for Gremlin in EMT observed in CAN.