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En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries
Published on: February 25, 2016
A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates
Chih-Hong Wang1, Feng Li, Sylvia Hiller
1Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599, USA.
Summary
Decreased endothelial nitric oxide synthase (eNOS) expression worsens diabetic kidney disease, increasing albuminuria and glomerular damage. However, it surprisingly reduced oxidative stress and fibrosis in diabetic mice.
Area of Science:
- Nephrology
- Genetics
- Cardiovascular Biology
Background:
- Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene (NOS3) are linked to diabetic nephropathy.
- Direct evidence linking reduced eNOS expression to worsened diabetic kidney disease is limited.
Purpose of the Study:
- To investigate the impact of genetically reduced eNOS expression on diabetic nephropathy.
- To determine if modest decreases in eNOS expression exacerbate kidney disease in a diabetic mouse model.
Main Methods:
- Utilized F1 hybrid mice from a cross involving eNOS(+/-) and Akita diabetogenic mutation (Ins2(C96Y/+)).
- Generated eNOS(+/+), eNOS(+/-), and eNOS(-/-) mice, both diabetic and non-diabetic.
- Assessed kidney function, blood pressure, and histological markers of nephropathy.
Main Results:
- Reduced eNOS expression (heterozygous and null) in diabetic mice led to increased albuminuria, mesangial expansion, glomerulosclerosis, and mesangiolysis, independent of blood pressure.
- Glomerular basement membrane thickening correlated with elevated blood pressure.
- Surprisingly, decreased eNOS ameliorated diabetes-induced oxidative stress and tubulointerstitial fibrosis.
Conclusions:
- Modest reductions in eNOS expression, similar to human NOS3 variants, significantly worsen diabetic nephropathy.
- The effects on kidney damage are partly independent of blood pressure changes.
- Reduced eNOS has complex, dual effects, exacerbating some aspects of nephropathy while ameliorating others like fibrosis.
