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Publication : Exacerbation of diabetic renal alterations in mice lacking vasohibin-1.

First Author  Hinamoto N Year  2014
Journal  PLoS One Volume  9
Issue  9 Pages  e107934
PubMed ID  25255225 Mgi Jnum  J:220626
Mgi Id  MGI:5635750 Doi  10.1371/journal.pone.0107934
Citation  Hinamoto N, et al. (2014) Exacerbation of diabetic renal alterations in mice lacking vasohibin-1. PLoS One 9(9):e107934
abstractText  Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocin-induced type 1 diabetic VASH1 heterozygous knockout mice (VASH1(+/-)) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1(+/-) mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickening and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-kappaB p65 were significantly exacerbated in the diabetic VASH1(+/-) mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of IkappaBalpha, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31(+) endothelial area was also increased in the diabetic VASH1(+/-) mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-beta1/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1(+/-) mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the development of diabetic renal alterations, partly via direct effects on podocytes, and thus, a strategy to recover VASH1 might potentially lead to the development of a novel therapeutic approach for diabetic nephropathy.
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