title: Targeted glomerular angiopoietin-1 therapy for early diabetic kidney disease.
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.
authors.affiliation: Cardiovascular Division, King's College London, London, United Kingdom;
authors.forename: Cecile
authors.initials: C
authors.lastname: Dessapt-Baradez
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: White
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Pan
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Huang
authors.forename: Anthea A
authors.initials: AA
authors.lastname: Hayward
authors.forename: Karen L
authors.initials: KL
authors.lastname: Price
authors.forename: Maria
authors.initials: M
authors.lastname: Kolatsi-Joannou
authors.forename: Maelle
authors.initials: M
authors.lastname: Locatelli
authors.forename: Marine
authors.initials: M
authors.lastname: Diennet
authors.forename: Zoe
authors.initials: Z
authors.lastname: Webster
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Smillie
authors.forename: Viji
authors.initials: V
authors.lastname: Nair
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: David A
authors.initials: DA
authors.lastname: Long
authors.forename: Luigi
authors.initials: L
authors.lastname: Gnudi
mesh_terms: D042683:Angiopoietin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D012333:RNA, Messenger; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2