title: Gremlin regulates renal inflammation via the vascular endothelial growth factor receptor 2 pathway.
abstract: Inflammation is a main feature of progressive kidney disease. Gremlin binds to bone morphogenetic proteins (BMPs), acting as an antagonist and regulating nephrogenesis and fibrosis among other processes. Gremlin also binds to vascular endothelial growth factor receptor-2 (VEGFR2) in endothelial cells to induce angiogenesis. In renal cells, gremlin regulates proliferation and fibrosis, but there are no data about inflammatory-related events. We have investigated the direct effects of gremlin in the kidney, evaluating whether VEGFR2 is a functional gremlin receptor. Administration of recombinant gremlin to murine kidneys induced rapid and sustained activation of VEGFR2 signalling, located in proximal tubular epithelial cells. Gremlin bound to VEGFR2 in these cells in vitro, activating this signalling pathway independently of its action as an antagonist of BMPs. In vivo, gremlin caused early renal damage, characterized by activation of the nuclear factor (NF)-κB pathway linked to up-regulation of pro-inflammatory factors and infiltration of immune inflammatory cells. VEGFR2 blockade diminished gremlin-induced renal inflammatory responses. The link between gremlin/VEGFR2 and NF-κB/inflammation was confirmed in vitro. Gremlin overexpression was associated with VEGFR2 activation in human renal disease and in the unilateral ureteral obstruction experimental model, where VEGFR2 kinase inhibition diminished renal inflammation. Our data show that a gremlin/VEGFR2 axis participates in renal inflammation and could be a novel target for kidney disease.
authors: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, REDINREN, Spain.
authors: Carolina
authors: C
authors: Lavoz
authors: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, REDINREN, Spain.
authors: Matilde
authors: M
authors: Alique
authors: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, REDINREN, Spain.
authors: Raquel
authors: R
authors: Rodrigues-Diez
authors: VichemChemie Ltd, Budapest, Hungary.
authors: Janos
authors: J
authors: Pato
authors: VichemChemie Ltd, Budapest, Hungary.|MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
authors: Gyorgy
authors: G
authors: Keri
authors: Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile.
authors: Sergio
authors: S
authors: Mezzano
authors: Division of Nephrology and Hypertension. IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, CIBERDEM, Madrid, Spain.
authors: Jesús
authors: J
authors: Egido
authors: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, REDINREN, Spain.
authors: Marta
authors: M
authors: Ruiz-Ortega
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D012189:Retrospective Studies; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014517:Ureteral Obstruction / Q000150:complications; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D040301:Vascular Endothelial Growth Factor Receptor-2; C113178:Grem1 protein, mouse; C486399:GREM1 protein, human; C000588866:KDR protein, human; C000592875:Kdr protein, mouse
keywords: NF-κB; VEGFR2; gremlin; inflammation