Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease.
Authors Dessapt-Baradez C, Woolf AS, White KE, Pan J, 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
Submitted By Submitted Externally on 12/20/2013
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2013
Date Published 9/5/2013
Volume : Pages 25 : 33 - 42
PubMed Reference 24009238
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.

Investigators with authorship
Matthias KretzlerUniversity of Michigan