Gremlin aggravates hyperglycemia‐induced podocyte injury by a TGFβ/smad dependent signaling pathway

Li, Guiying; Li, Ying; Liu, Shuxia; Shi, Yonghong; Chi, Yue; Liu, Guijing; Shan, Tieying

doi:10.1002/jcb.24559

Cited by 42 publications

(37 citation statements)

References 38 publications

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“…This is consistent with the effect of glucose on Smurf-1 ( Figure 5) and other ubiquitin ligases (59), as well as with the role of hyperglycemia on Gremlin-1 in podocyte injury (60) and cell proliferation in mesangial cells (61). It is possible that Smurf-1 is regulated by glucose uptake/metabolism by mechanisms similar to those of Gremlin-1, in which transforming growth factor b-1 (TGFb-1) signaling pathways are amplified (60,62). Indeed, dysregulated TGFb-1 signaling has been documented in pulmonary hypertension (63,64), has opposing effects on BMP signaling (65,66), and can up-regulate the expression of Smurf proteins (67,68).…”

Section: Original Researchsupporting

confidence: 88%

“…Previous reports have shown that Gremlin-1 expression can also be stimulated by increasing glucose levels (Gremlin-1 was once termed increased-in-high-glucoseprotein-2) (58). This is consistent with the effect of glucose on Smurf-1 ( Figure 5) and other ubiquitin ligases (59), as well as with the role of hyperglycemia on Gremlin-1 in podocyte injury (60) and cell proliferation in mesangial cells (61). It is possible that Smurf-1 is regulated by glucose uptake/metabolism by mechanisms similar to those of Gremlin-1, in which transforming growth factor b-1 (TGFb-1) signaling pathways are amplified (60,62).…”

Section: Original Researchsupporting

confidence: 80%

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Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Barnes¹,

Kucera²,

Tian³

et al. 2016

Am J Respir Cell Mol Biol

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Altered bone morphogenic protein (BMP) signaling, independent of BMPR2 mutations, can result in idiopathic pulmonary arterial hypertension (IPAH). Glucose dysregulation can regulate multiple processes in IPAH. However, the role of glucose in BMP antagonist expression in IPAH has not been characterized. We hypothesized that glucose uptake regulates BMP signaling through stimulation of BMP antagonist expression in IPAH. Using human plasma, lung tissue, and primary pulmonary arterial smooth muscle cells (PASMCs), we examined the protein expression of BMP2, BMP-regulated Smads, and Smurf-1 in patients with IPAH and control subjects. Gremlin-1 levels were elevated in patients with IPAH compared with control subjects, whereas expression of BMP2 was not different. We demonstrate increased Smad polyubiquitination in IPAH lung tissue and PASMCs that was further enhanced with proteasomal inhibition. Examination of the Smad ubiquitin-ligase, Smurf-1, showed increased protein expression in IPAH lung tissue and localization in the smooth muscle of the pulmonary artery. Glucose dose dependently increased Smurf-1 protein expression in control PASMCs, whereas Smurf-1 in IPAH PASMCs was increased and sustained. Conversely, phosphoSmad1/5/8 levels were reduced in IPAH compared with control PASMCs at physiological glucose concentrations. Interestingly, high glucose concentrations decreased phosphorylation of Smad1/5/8 in control PASMCs. Blocking glucose uptake had opposing effects in IPAH PASMCs, and inhibition of Smurf-1 activity resulted in partial rescue of Smad1/5/8 activation and cell migration rates. Collectively, these data suggest that BMP signaling can be regulated through BMPR2 mutation-independent mechanisms. Gremlin-1 (synonym: induced-in-high-glucose-2 protein) and Smurf-1 may function to inhibit BMP signaling as a consequence of the glucose dysregulation described in IPAH.

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Section: Original Researchsupporting

confidence: 88%

Section: Original Researchsupporting

confidence: 80%

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Barnes¹,

Kucera²,

Tian³

et al. 2016

Am J Respir Cell Mol Biol

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“…20,21 In both B6 and SJL mice, TGF-b apparently was strongly induced by exposure to GREM1. The complementary regulation of TGF-b and GREM1 was observed recently in podocytes exposed to high-glucose conditions 40 and in renal tubular epithelial cells, 41 where GREM1 was involved in TGF-beinduced EMT. On the contrary, it appears as though GREM1 is induced by TGF-b in the peritoneum of B6 mice but not SJL mice.…”

Section: Discussionmentioning

confidence: 92%

Gremlin Promotes Peritoneal Membrane Injury in an Experimental Mouse Model and Is Associated with Increased Solute Transport in Peritoneal Dialysis Patients

Siddique

Curran

Ghayur

et al. 2014

The American Journal of Pathology

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The peritoneal membrane becomes damaged in patients on peritoneal dialysis (PD). Gremlin 1 (GREM1) inhibits bone morphogenic proteins (BMPs) and plays a role in kidney development and fibrosis. We evaluated the role of gremlin in peritoneal fibrosis and angiogenesis. In a cohort of 32 stable PD patients, GREM1 concentration in the peritoneal effluent correlated with measures of peritoneal membrane damage. AdGrem1, an adenovirus to overexpress gremlin in the mouse peritoneum, induced submesothelial thickening, fibrosis, and angiogenesis in C57BL/6 mice, which was associated with decreased expression of BMP4 and BMP7. There was evidence of mesothelial cell transition to a mesenchymal phenotype with increased α smooth muscle actin expression and suppression of E-cadherin. Some of the GREM1 effects may be reversed with recombinant BMP7 or a pan-specific transforming growth factor β (TGF-β) antibody. Neovascularization was not inhibited with a TGF-β antibody, suggesting a TGF-β-independent angiogenic mechanism. Swiss/Jackson Laboratory (SJL) mice, which are resistant to TGF-β-induced peritoneal fibrosis, responded in a similar fashion to AdGrem1 as did C57BL/6 mice with fibrosis, angiogenesis, and mesothelial-to-mesenchymal transition. GREM1 was associated with up-regulated TGF-β expression in both SJL and C57BL/6 mice, but SJL mice demonstrated a defective TGF-β-induced GREM1 expression. In summary, GREM1 induces fibrosis and angiogenesis in mouse peritoneum and is associated with increased solute transport in these PD patients.

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“…51 Although its contribution to neovascularization and tumor growth in experimental and human neoplasms deserves further investigation, our data support the notion that gremlin produced by tumor cells may induce angiogenesis by interacting directly with ECs and by stimulating the recruitment of a proangiogenic inflammatory infiltrate. Accordingly, previous observations have shown that gremlin upregulation may play a pathogenic role in different chronic inflammatory conditions, including hypoxic pulmonary hypertension, 52 diabetic nephropathy, 53 and lung fibrosis. 54 Indeed, gremlin haplodeficiency reduces vascular remodeling in hypoxic lung and diabetes mellitus-associated kidney damage.…”

Section: Discussionmentioning

confidence: 97%

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Corsini

Moroni

Ravelli

et al. 2014

ATVB

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Objective-Angiogenesis and inflammation are closely related processes. Gremlin is a novel noncanonical vascular endothelial growth factor receptor-2 (VEGFR2) ligand that induces a proangiogenic response in endothelial cells (ECs).Here, we investigated the role of the cyclic adenosine monophosphate-response element (CRE)-binding protein (CREB) in mediating the proinflammatory and proangiogenic responses of ECs to gremlin. Approach and Results-Gremlin induces a proinflammatory response in ECs, leading to reactive oxygen species and cyclic adenosine monophosphate production and the upregulation of proinflammatory molecules involved in leukocyte extravasation, including chemokine (C-C motif) ligand-2 (Ccl2) and Ccl7, chemokine (C-X-C motif) ligand-1 (Cxcl1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). Accordingly, gremlin induces the VEGFR2-dependent phosphorylation, nuclear translocation, and transactivating activity of CREB in ECs. CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to monocyte/macrophage adhesion to ECs and their extravasation. All these effects are inhibited by EC transfection with a dominant-negative CREB mutant or with a CREB-binding protein-CREB interaction inhibitor that competes for CREB/CRE binding. Also, both recombinant gremlin and gremlin-expressing tumor cells induce proinflammatory/proangiogenic responses in vivo that are suppressed by the anti-inflammatory drug hydrocortisone. Corsini et al CREB in Gremlin Activity 137diseases 24 and cancer. [25][26][27] Gremlin acts as a bone morphogenic protein (BMP) antagonist by binding BMP2, BMP4, and BMP7. 28 Also, gremlin stimulates EC intracellular signaling and motility in a BMP-independent manner, leading to a potent angiogenic response in vivo. 27,29 This is because of the capacity of gremlin to bind and activate VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals. 30,31 Also, gremlin interacts with heparan-sulfate proteoglycans that act as functional gremlin coreceptors in ECs, affecting its productive interaction with VEGFR2.32 However, at variance with heparin-binding VEGFs, gremlin does not interact with the coreceptor neuropilin-1. 32 Thus, gremlin is a novel proangiogenic VEGFR2 agonist distinct from canonical VEGFs.Here, we demonstrate that gremlin induces a proinflammatory response in ECs by inducing the expression of various chemokines and cell adhesion molecules, causing a VEGFR2-mediated activation of CREB. In turn, CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to leukocyte-adhesion to ECs and their extravasation. In keeping with these observations, gremlin and gremlin-expressing tumor cells induce a proinflammatory or proangiogenic response in vivo that is suppressed by the anti-inflammatory drug hydrocortisone. These data point to a nonredundant role of CRE...

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Gremlin aggravates hyperglycemia‐induced podocyte injury by a TGFβ/smad dependent signaling pathway

Cited by 42 publications

References 38 publications

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Gremlin Promotes Peritoneal Membrane Injury in an Experimental Mouse Model and Is Associated with Increased Solute Transport in Peritoneal Dialysis Patients

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

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