| 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 |
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| 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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