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

Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile.
Transplantation Proceedings (Impact Factor: 0.98). 05/2008; 40(3):734-9. DOI: 10.1016/j.transproceed.2008.02.064
Source: PubMed


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.
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.
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.
We postulated that Gremlin is a downstream mediator of TGF-beta, suggesting a role for Gremlin in EMT observed in CAN.

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    • "In biopsies obtained from patients with diabetic nephropathy, we have observed gremlin expression in areas with tubule-interstitial fibrosis, and it colocalizes with transforming growth factor-β (TGF-β) [9]. Moreover, gremlin is also expressed in cellular glomerular crescents and in the tubular and infiltrating interstitial cells of human biopsies of pauci-immune glomerulonephritis and chronic allograft nephropathy, broadening the range of activity to a more global role for gremlin in renal diseases [10], [11]. We have recently shown that recombinant gremlin directly regulates profibrotic events in cultured tubulo-interstitial cells and acts as a mediator of TGF-β responses [12]. "
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    ABSTRACT: A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This transgenic mouse model could be used as a new tool for enhancing the knowledge of renal disease progression.
    PLoS ONE 07/2014; 9(7):e101879. DOI:10.1371/journal.pone.0101879 · 3.23 Impact Factor
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    • "We have also reported the presence of Gremlin in glomerular crescents of human pauci-immune glomerulonephritis and in the tubulointerstitium of chronic allograft nephropathy. In these human diseases Gremlin correlated with the degree of tubulointerstitial fibrosis and was associated with TGF-í µí»½1 overexpression and Smad pathway activation [7] [8]. These studies suggest that Gremlin may activate the Smad pathway; therefore, the aim of this work was to evaluate whether Gremlin could directly activate the Smad pathway in tubular epithelial cells, evaluating whether this activation is linked to Gremlin-induced EMT, the main fibrotic effect observed in response to Gremlin stimulation in these cells [18] "
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    ABSTRACT: Gremlin is a developmental gene upregulated in human chronic kidney disease and in renal cells in response to transforming growth factor- β (TGF- β ). Epithelial mesenchymal transition (EMT) is one process involved in renal fibrosis. In tubular epithelial cells we have recently described that Gremlin induces EMT and acts as a downstream TGF- β mediator. Our aim was to investigate whether Gremlin participates in EMT by the regulation of the Smad pathway. Stimulation of human tubular epithelial cells (HK2) with Gremlin caused an early activation of the Smad signaling pathway (Smad 2/3 phosphorylation, nuclear translocation, and Smad-dependent gene transcription). The blockade of TGF- β , by a neutralizing antibody against active TGF- β , did not modify Gremlin-induced early Smad activation. These data show that Gremlin directly, by a TGF- β independent process, activates the Smad pathway. In tubular epithelial cells long-term incubation with Gremlin increased TGF- β production and caused a sustained Smad activation and a phenotype conversion into myofibroblasts-like cells. Smad 7 overexpression, which blocks Smad 2/3 activation, diminished EMT changes observed in Gremlin-transfected tubuloepithelial cells. TGF- β neutralization also diminished Gremlin-induced EMT changes. In conclusion, we propose that Gremlin could participate in renal fibrosis by inducing EMT in tubular epithelial cells through activation of Smad pathway and induction of TGF- β .
    BioMed Research International 05/2014; 2014. DOI:10.1155/2014/802841 · 2.71 Impact Factor
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    ABSTRACT: Long-term peritoneal dialysis (PD) can lead to fibrotic changes in the peritoneum, characterized by loss of mesothelial cells (MCs) and thickening of the submesothelial area with an accumulation of collagen and myofibroblasts. The origin of myofibroblasts is a central question in peritoneal fibrosis that remains unanswered at present. Numerous clinical and experimental studies have suggested that MCs, through epithelial-mesenchymal transition (EMT), contribute to the pool of peritoneal myofibroblasts. However, recent work has placed significant doubts on the paradigm of EMT in organ fibrogenesis (in the kidney particularly), highlighting the need to reconsider the role of EMT in the generation of myofibroblasts in peritoneal fibrosis. In particular, selective cell isolation and lineage-tracing experiments have suggested the existence of progenitor cells in the peritoneum, which are able to switch to fibroblast-like cells when stimulated by the local environment. These findings highlight the plastic nature of MCs and its contribution to peritoneal fibrogenesis. In this review, we summarize the key findings and caveats of EMT in organ fibrogenesis, with a focus on PD-related peritoneal fibrosis, and discuss the potential of peritoneal MCs as a source of myofibroblasts. Copyright © 2015 International Society for Peritoneal Dialysis.
    Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis 02/2015; 35(1):14-25. DOI:10.3747/pdi.2014.00188 · 1.53 Impact Factor
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