The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy.
A growing body of evidence implicates inflammation in the development of diabetic nephropathy. We recently reported that diabetic endothelial nitric oxide synthase knockout (eNOS KO) mice develop advanced glomerular lesions resembling human diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a major factor in diabetic nephropathy, and is known to be chemotactic for macrophages. Herein, we examined the association of VEGF with macrophage infiltration in experimental diabetic nephropathy. Glomerular macrophage infiltration was markedly increased in diabetic eNOS KO mice compared to diabetic C57BL/6 mice, and correlated with glomerular injury, such as mesangiolysis, glomerular microaneurysm and nodular lesions of glomerular sclerosis. An elevation of podocyte VEGF expression correlated with infiltration of Flt-1-positive macrophage in injured glomeruli in diabetic eNOS KO mice, suggesting that VEGF could contribute to macrophage migration. Neither renal nNOS nor iNOS expression was altered in both C57BL/6 and eNOS KO mice. To determine if lack of NO could affect VEGF activation of macrophages, we examined if exogenous NO can block macrophage migration induced by VEGF in in vitro studies. Exogenous NO blocked macrophage migration and hypertrophy in response to VEGF. NO mediated these effects in part by downregulating Flt-1 expression on the macrophage. In summary, NO negatively regulates VEGF-induced macrophage migration by inhibiting Flt-1 expression. The VEGF-endothelial NO uncoupling pathway might partially explain how VEGF causes glomerular disease in diabetes.
Sato
Waichi
W
Division of Nephrology, Department of Medicine, University of Florida, Gainesville, FL 32610-0224, USA.
Kosugi
Tomoki
T
Zhang
Li
L
Roncal
Carlos A
CA
Heinig
Marcelo
M
Campbell-Thompson
Martha
M
Yuzawa
Yukio
Y
Atkinson
Mark A
MA
Grant
Maria B
MB
Croker
Byron P
BP
Nakagawa
Takahiko
T
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III