Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat...

Area of Science:

• Nephrology
• Cardiovascular Research
• Metabolic Diseases

Background:

• Endothelial nitric oxide synthase (eNOS) deficiency accelerates diabetic nephropathy (DN).
• Diabetes and eNOS deficiency are linked to increased fibrin deposition and tissue factor (TF) via inflammatory pathways.
• TF is implicated in the pathogenesis of DN, particularly under conditions of metabolic stress.

Purpose of the Study:

• To investigate the role of TF in exacerbating DN in eNOS knockout (eNOS-/-) mice fed a high-fat (HF) diet.
• To determine if TF contributes to the increased severity of DN observed in diabetic eNOS-/- mice on an HF diet.

Main Methods:

• Diabetic eNOS-/- and wild-type mice were induced using streptozotocin.
• Mice were fed either a standard or a high-fat (HF) diet.
• Kidney pathology, albuminuria, fibrin deposition, TF expression, and inflammatory gene expression were assessed.

Main Results:

• Lack of eNOS significantly worsened DN, increasing albuminuria, glomerulosclerosis, fibrosis, and GBM thickness.
• HF diet alone did not affect DN in wild-type mice but markedly exacerbated DN in eNOS-/- mice.
• TF and fibrin levels increased additively with eNOS deficiency and HF diet, preceding DN development.
• TF inhibition reduced inflammatory gene expression in diabetic mice.

Conclusions:

• TF plays a causal role in the exacerbation of DN in eNOS deficient mice.
• High-fat diet worsens DN in eNOS deficient mice by enhancing inflammatory responses mediated by TF.