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Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease

Lookup NU author(s): Dr Kathryn White


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Vascular growth factors play an important role in maintaining the structure and integrity of the glomerular filtration barrier. In healthy adult glomeruli, the proendothelial survival factors vascular endothelial growth factor-A (VEGF-A) and angiopoietin-1 are constitutively expressed in glomerular podocyte epithelia. We demonstrate that this milieu of vascular growth factors is altered in streptozotocin-induced type 1 diabetic mice, with decreased angiopoietin-1 levels, VEGF-A upregulation, decreased soluble VEGF receptor-1 (VEGFR1), and increased VEGFR2 phosphorylation. This was accompanied by marked albuminuria, nephromegaly, hyperfiltration, glomerular ultrastructural alterations, and aberrant angiogenesis. We subsequently hypothesized that restoration of angiopoietin-1 expression within glomeruli might ameliorate manifestations of early diabetic glomerulopathy. Podocyte-specific inducible repletion of angiopoietin-1 in diabetic mice caused a 70% reduction of albuminuria and prevented diabetes-induced glomerular endothelial cell proliferation; hyperfiltration and renal morphology were unchanged. Furthermore, angiopoietin-1 repletion in diabetic mice increased Tie-2 phosphorylation, elevated soluble VEGFR1, and was paralleled by a decrease in VEGFR2 phosphorylation and increased endothelial nitric oxide synthase Ser(1177) phosphorylation. Diabetes-induced nephrin phosphorylation was also reduced in mice with angiopoietin-1 repletion. In conclusion, targeted angiopoietin-1 therapy shows promise as a renoprotective tool in the early stages of diabetic kidney disease.

Publication metadata

Author(s): Dessapt-Baradez C, Woolf AS, White KE, Pan JQ, Huang JL, Hayward AA, Price KL, Kolatsi-Joannou M, Locatelli M, Diennet M, Webster Z, Smillie SJ, Nair V, Kretzler M, Cohen CD, Long DA, Gnudi L

Publication type: Article

Publication status: Published

Journal: Journal of the American Society of Nephrology

Year: 2014

Volume: 25

Issue: 1

Pages: 33-42

Print publication date: 01/01/2014

ISSN (print): 1046-6673

ISSN (electronic): 1533-3450

Publisher: American Society of Nephrology


DOI: 10.1681/ASN.2012121218


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Funder referenceFunder name
Manchester Academic Health Science Centre
KRUK Senior Non-Clinical Fellowship
Manchester Biomedical Research Centre
MRC New Investigator Award
08/0003695Diabetes UK
P30-DK081943George M. O'Brien Kidney Research Core Centre