Elevated tissue factor expression contributes to exacerbated diabetic
nephropathy in mice lacking eNOS fed a high fat diet
Authors F . L I , C.-H. WANG, J .-G. WANG, T. THAI , G. BOYSEN, L . XU, A. L . TURNER,
Submitted By Oliver Smithies on 11/8/2010
Status Published
Journal Journal of thrombosis and haemostasis : JTH
Year 2010
Date Published 10/1/2010
Volume : Pages 8 : 2122 - 2132
PubMed Reference 20626618
Abstract Human eNOS (NOS3) polymorphisms
that lower its expression are associated with advanced
diabetic nephropathy (DN), and the lack of eNOS accelerates
DN in diabetic mice. Diabetes is associated with fibrin
deposition. Lack of nitric oxide and fatty acids stimulates the
NF-kB pathway, which increases tissue factor (TF). Objectives:
To test the hypothesis that TF contributes to the severity ofDN
in the diabetic eNOS)/) mice fed a high-fat diet (HF). Methods:
We made eNOS)/) and wild-type mice diabetic with streptozotocin.
Half of them were placed on HF. Results: Blood
glucose levels were not affected by either the diet or eNOS
genotype. Lack of eNOS in the diabetic mice increased urinary
albumin excretion, glomerulosclerosis, interstitial fibrosis, and
glomerular basement membrane thickness. HF by itself did not
affect DNin the wild-typemice, but significantly enhancedDN
in eNOS)/) mice. More than half of diabetic eNOS)/) mice on
HF died prematurely with signs of thrombotic complications.
Diabetic kidneys contained fibrin and TF, and their levels were
increased by the lack ofeNOSand byHFin an additive fashion.
The HF diet increased the kidney expression of inflammatory
genes. The increase in TF preceded DN, and administration of
an anti-mouse TF antibody to diabetic mice reduced the
expression of inflammatory genes. Conclusion: Together, these
data indicate a causal link between TF and the exacerbation of
DN in eNOS)/) mice. The condition is significantly worsened
by enhanced inflammatory responses to an HF diet via TF.

Investigators with authorship
Nobuyo MaedaUniversity of North Carolina
Oliver SmithiesUniversity of North Carolina