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Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease

Research output: Contribution to journalArticle

Cecile Dessapt-Baradez, Adrian S Woolf, Kathryn E White, Jiaqi Pan, Jennifer L Huang, Anthea A Hayward, Karen L Price, Maria Kolatsi-Joannou, Maelle Locatelli, Marine Diennet, Zoe Webster, Sarah J Smillie, Viji Nair, Matthias Kretzler, Clemens D Cohen, David A Long, Luigi Gnudi

Original languageEnglish
Article numberN/A
Pages (from-to)N/A
JournalJournal of the American Society of Nephrology
VolumeN/A
Issue numberN/A
DOIs
Publication statusE-pub ahead of print - 2013

King's Authors

Abstract

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.

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