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Open AccessArticle

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

1
Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, Bueras 1003, Valdivia, Chile
2
Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Reyes Católicos 2, 28040 Madrid, Spain
3
Red de Investigación Renal (REDINREN), 28040 Madrid, Spain
4
Unidad Microscopía Electrónica, Vice-Rectoria de Investigación, Desarrollo y Creación Artística, Universidad Austral de Chile, Independencia 631, Valdivia, Chile
5
Renal, Vascular and Diabetes Research Laboratory. Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
6
Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(2), 302; https://doi.org/10.3390/jcm9020302
Received: 24 December 2019 / Revised: 14 January 2020 / Accepted: 16 January 2020 / Published: 21 January 2020
(This article belongs to the Special Issue Diabetic Nephropathy: Diagnosis, Prevention and Treatment)
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. View Full-Text
Keywords: VEGFR2; VEGFA; GREMLIN; inflammation; podocytes; diabetes; diabetic nephropathy; tubular cells VEGFR2; VEGFA; GREMLIN; inflammation; podocytes; diabetes; diabetic nephropathy; tubular cells
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MDPI and ACS Style

Lavoz, C.; Rodrigues-Diez, R.R.; Plaza, A.; Carpio, D.; Egido, J.; Ruiz-Ortega, M.; Mezzano, S. VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy. J. Clin. Med. 2020, 9, 302.

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