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      Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy.

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          Abstract

          Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF-A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.

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          Author and article information

          Journal
          J. Am. Soc. Nephrol.
          Journal of the American Society of Nephrology : JASN
          1533-3450
          1046-6673
          Aug 2015
          : 26
          : 8
          Affiliations
          [1 ] School of Physiology and Pharmacology and.
          [2 ] School of Physiology and Pharmacology and Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom;
          [3 ] School of Life Sciences and.
          [4 ] Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom;
          [5 ] Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institut, Villigen, Switzerland;
          [6 ] School of Physiology and Pharmacology and School of Life Sciences and.
          [7 ] Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; and.
          [8 ] Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
          [9 ] Cancer Biology, Division of Oncology, School of Medicine, University of Nottingham, Nottingham, United Kingdom;
          [10 ] School of Physiology and Pharmacology and Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom; Andy.Salmon@bristol.ac.uk David.Bates@nottingham.ac.uk.
          Article
          ASN.2014040350
          10.1681/ASN.2014040350
          4520162
          25542969
          4ae05142-7f61-46b7-8d2f-c1d74e4413fe
          Copyright © 2015 by the American Society of Nephrology.
          History

          VEGF,VEGF-A,albuminuria,diabetes,diabetic nephropathy,endothelial glycocalyx,glomerulus,glycocalyx,permeability

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