No evidence of Gremlin1-mediated activation of VEGFR2 signaling in endothelial cells

Dutton, Louise; O'Neill, Christina; Medina, Reinhold J.; Brazil, Derek P.

doi:10.1074/jbc.ac119.010148

Cited by 13 publications

(13 citation statements)

References 45 publications

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“…Gremlin 1 is a member of the DAN family of protein antagonists, primarily inhibiting BMP2 and BMP4, but has also been found to have other non-BMP binding partners such as the Slit protein in monocytes and, unexpectedly, also vascular endothelial growth factor receptor 2 with effects on angiogenesis (26). However, vascular endothelial growth factor receptor 2 as a binding partner could not be confirmed in a recent extensive study (27). It is also unlikely that the inhibitory effects of Gremlin 1 on insulin signaling, which are seen very rapidly (within a few hours), can be accounted for by its inhibitory effects on adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH

et al. 2020

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The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.

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Section: Discussionmentioning

confidence: 99%

The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH

et al. 2020

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“…The vascular endothelial growth factor receptor 2 (VEGFR2) is expressed in several renal cells, including podocytes and tubular epithelial cells [4,5]. This receptor is activated in experimental and human renal diseases [6], including DN [7].…”

Section: Introductionmentioning

confidence: 99%

VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy

Lavoz

Rodrigues-Díez

Plaza

et al. 2020

JCM

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The absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the effects of its blockade in experimental models of DN is still controversial. Here, we test the effects of a therapeutic anti-VEGFR2 treatment, using a VEGFR2 kinase inhibitor, on the progression of renal damage in the BTBR ob/ob (leptin deficiency mutation) mice. This experimental diabetic model develops histological characteristics mimicking the key features of advanced human DN. A VEGFR2 pathway-activation blockade using the VEGFR2 kinase inhibitor SU5416, starting after kidney disease development, improves renal function, glomerular damage (mesangial matrix expansion and basement membrane thickening), tubulointerstitial inflammation and tubular atrophy, compared to untreated diabetic mice. The downstream mechanisms involved in these beneficial effects of VEGFR2 blockade include gene expression restoration of podocyte markers and downregulation of renal injury biomarkers and pro-inflammatory mediators. Several ligands can activate VEGFR2, including the canonical ligands VEGFs and GREMLIN. Activation of a GREMLIN/VEGFR2 pathway, but not other ligands, is correlated with renal damage progression in BTBR ob/ob diabetic mice. RNA sequencing analysis of GREMLIN-regulated genes confirm the modulation of proinflammatory genes and related-molecular pathways. Overall, these data show that a GREMLIN/VEGFR2 pathway activation is involved in diabetic kidney disease and could potentially be a novel therapeutic target in this clinical condition.

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“…We found addition of recombinant protein GREM1 during Stage 3 increased the phosphorylation of VEGFR2, Akt and p42/44MAPK, which were important in the proliferation. This is clear and interesting as a very recent report, highlighted that GREM1 did not induce phosphorylation in endothelial cells 27 . To find out why the results are different, we used two different pVEGFR2 antibody; one was pVEGFR2 (Tyr1054, Tyr1059) polyclonal antibody, and the other was pVEGFR2(pTyr1175).…”

Section: Discussionmentioning

confidence: 77%

Stage‐specific regulation of Gremlin1 on the differentiation and expansion of human urinary induced pluripotent stem cells into endothelial progenitors

Chen

Zhang

Wang

et al. 2020

J Cellular Molecular Medi

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Human urinary induced pluripotent stem cells (hUiPSCs) produced from exfoliated renal epithelial cells present in urine may provide a non‐invasive source of endothelial progenitors for the treatment of ischaemic diseases. However, their differentiation efficiency is unsatisfactory and the underlying mechanism of differentiation is still unknown. Gremlin1 (GREM1) is an important gene involved in cell differentiation. Therefore, we tried to elucidate the roles of GREM1 during the differentiation and expansion of endothelial progenitors. HUiPSCs were induced into endothelial progenitors by three stages. After differentiation, GREM1 was obviously increased in hUiPSC‐induced endothelial progenitors (hUiPSC‐EPs). RNA interference (RNAi) was used to silence GREM1 expression in three stages, respectively. We demonstrated a stage‐specific effect of GREM1 in decreasing hUiPSC‐EP differentiation in the mesoderm induction stage (Stage 1), while increasing differentiation in the endothelial progenitors' induction stage (Stage 2) and expansion stage (Stage 3). Exogenous addition of GREM1 recombinant protein in the endothelial progenitors' expansion stage (Stage 3) promoted the expansion of hUiPSC‐EPs although the activation of VEGFR2/Akt or VEGFR2/p42/44MAPK pathway. Our study provided a new non‐invasive source for endothelial progenitors, demonstrated critical roles of GREM1 in hUiPSC‐EP and afforded a novel strategy to improve stem cell‐based therapy for the ischaemic diseases.

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No evidence of Gremlin1-mediated activation of VEGFR2 signaling in endothelial cells

Cited by 13 publications

References 45 publications

The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH

The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH

VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy

Stage‐specific regulation of Gremlin1 on the differentiation and expansion of human urinary induced pluripotent stem cells into endothelial progenitors

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