VEGFR2 blockade improves renal damage in an experimental model of type 2 diabetic nephropathy
Entidad
Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD); UAM. Departamento de MedicinaEditor
MDPI, Basel, SwitzerlandFecha de edición
2020-01-21Cita
10.3390/jcm9020302
Journal of Clinical Medicine 9.2 (2020): 302
ISSN
2077-0383DOI
10.3390/jcm9020302Financiado por
This research was funded by Fondecyt 1160465 to S.M., e Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (Grants PI17/00119 and Red de Investigación Renal REDINREN: RD16/0009 to M.R.-O; and PI17/01495 to J.E.). Comunidad de Madrid (Grant “NOVELREN” B2017/BMD-3751 to M.R.-O).Proyecto
Gobierno de España. PI17/00119; Gobierno de España. RD16/0009; Gobierno de España. PI17/01495 to; Comunidad de Madrid. B2017/BMD-375/NOVELRENVersión del editor
10.3390/jcm9020302Materias
VEGFR2; VEGFA; GREMLIN; Inflammation; Podocytes; Diabetes; Diabetic nephropathy; Tubular cells; MedicinaDerechos
© 2020 The AuthorsResumen
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 e ects of its blockade
in experimental models of DN is still controversial. Here, we test the e ects 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 e ects 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
Lista de ficheros
Google Scholar:Lavoz, Carolina
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Rodrigues-Diez, Raul R.
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Plaza, Anita
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Carpio, Daniel
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Egido, Jesús
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Ruiz Ortega, Marta
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Mezzano, Sergio
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