Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy

Universidad Austral de Chile, Ciudad de Valdivía, Los Ríos, Chile
American Journal of Kidney Diseases (Impact Factor: 5.76). 07/2005; 45(6):1034-9. DOI: 10.1053/j.ajkd.2005.03.014
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "Abundant Gremlin expression also occurs in diabetic nephropathy [30] [31], occasionally in glomeruli, but most prominently in areas of tubulointerstitial fibrosis, where it colocalizes with TGF-í µí»½ and is directly correlated with renal dysfunction [32]. BMP-7 and Gremlin are involved in renal development and diabetic nephropathy and undergo expression changes in the diabetic kidney [33] [34]. Dolan and colleagues proposed that reactivation of Gremlin (and BMP-7) in the diabetic kidney is a novel therapeutic target for diabetic nephropathy, since administration of the Gremlin ligand BMP-7 is protective in models of progressive renal diseases [30]. "
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    ABSTRACT: Gremlin is an antagonist of bone morphogenetic protein (BMP) and a major driving force in skeletal modeling in the fetal stage. Several recent reports have shown that Gremlin is also involved in angiogenesis of lung cancer and diabetic retinopathy. The purpose of this study was to investigate the role of Gremlin in tumor angiogenesis in pituitary adenoma. Double fluorescence immunohistochemistry of Gremlin and CD34 was performed in pituitary adenoma tissues obtained during transsphenoidal surgery in 45 cases (7 PRLoma, 17 GHoma, 2 ACTHoma, and 2 TSHoma). Gremlin and microvascular density (MVD) were detected by double-immunofluorescence microscopy in CD34-positive vessels from tissue microarray analysis of 60 cases of pituitary adenomas (6 PRLoma, 23 GHoma, 22 NFoma, 5 ACTHoma, and 4 TSHoma). In tissue microarray analysis, MVD was significantly correlated with an increased Gremlin level (linear regression: P < 0.005, r (2) = 0.4958). In contrast, Gremlin expression showed no correlation with tumor subtype or Knosp score. The high level of expression of Gremlin in pituitary adenoma tissue with many CD34-positive vessels and the strong coherence of these regions indicate that Gremlin is associated with angiogenesis in pituitary adenoma cells.
    International Journal of Endocrinology 01/2015; 2015:834137. DOI:10.1155/2015/834137 · 1.52 Impact Factor
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    • "Gremlin is a glycosylated , phosphorylated, secreted protein present both on the external cell surface and within the ER-Golgi compartments [3]. In many human renal diseases induction of Gremlin has been described [5] [6] [7] [8]. Several experimental studies have shown that Gremlin participates in renal damage [9] [10]. "
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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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    • "Mice lacking Gremlin die shortly after birth due to renal agenesis [16]. Gremlin expression is low in normal, adult kidney but is highly expressed in areas of tubular fibrosis in kidneys from diabetic nephropathy patients [17]. Increased Gremlin expression during nephropathy fits within the paradigm of aberrant developmental gene expression during disease progression. "
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    ABSTRACT: Diabetic nephropathy is currently the leading cause of end-stage renal disease worldwide, and occurs in approximately one third of all diabetic patients. The molecular pathogenesis of diabetic nephropathy has not been fully characterized and novel mediators and drivers of the disease are still being described. Previous data from our laboratory has identified the developmentally regulated gene Gremlin as a novel target implicated in diabetic nephropathy in vitro and in vivo. We used bioinformatic analysis to examine whether Gremlin gene sequence and structure could be used to identify other genes implicated in diabetic nephropathy. The Notch ligand Jagged1 and its downstream effector, hairy enhancer of split-1 (Hes1), were identified as genes with significant similarity to Gremlin in terms of promoter structure and predicted microRNA binding elements. This led us to discover that transforming growth factor-beta (TGFbeta1), a primary driver of cellular changes in the kidney during nephropathy, increased Gremlin, Jagged1 and Hes1 expression in human kidney epithelial cells. Elevated levels of Gremlin, Jagged1 and Hes1 were also detected in extracts from renal biopsies from diabetic nephropathy patients, but not in control living donors. In situ hybridization identified specific upregulation and co-expression of Gremlin, Jagged1 and Hes1 in the same tubuli of kidneys from diabetic nephropathy patients, but not controls. Finally, Notch pathway gene clustering showed that samples from diabetic nephropathy patients grouped together, distinct from both control living donors and patients with minimal change disease. Together, these data suggest that Notch pathway gene expression is elevated in diabetic nephropathy, co-incident with Gremlin, and may contribute to the pathogenesis of this disease.
    Biochimica et Biophysica Acta 02/2008; 1782(1):10-21. DOI:10.1016/j.bbadis.2007.09.005 · 4.66 Impact Factor
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