Improvement of endothelial nitric oxide synthase activity retards the
progression of diabetic nephropathy in db/db mice.
Authors Cheng H, Wang H, Fan X, Paueksakon P, Harris RC
Submitted By Raymond Harris on 7/10/2013
Status Published
Journal Kidney international
Year 2012
Date Published 12/1/2012
Volume : Pages 82 : 1176 - 1183
PubMed Reference 22785174
Abstract Impaired endothelial nitric oxide synthase (eNOS) activity may be involved in
the pathogenesis of diabetic nephropathy. To test this, we used the type 2
diabetic db/db mouse (BKS background) model and found impaired eNOS dimerization
and phosphorylation along with moderate glomerular mesangial expansion and
increased glomerular basement membrane (GBM) thickness at 34 weeks of age.
Cultured murine glomerular endothelial cells exposed to high glucose had similar
alterations in eNOS dimerization and phosphorylation. Treatment with
sepiapterin, a stable precursor of the eNOS cofactor tetrahydrobiopterin, or the
nitric oxide precursor L-arginine corrected changes in eNOS dimerization and
phosphorylation, corrected permeability defects, and reduced apoptosis.
Sepiapterin or L-arginine, administered to db/db mice from weeks 26 to 34, did
not significantly alter hyperfiltration or affect mesangial expansion, but
reduced albuminuria and GBM thickness, and decreased urinary isoprostane and
nitrotyrosine excretion (markers of oxidative stress). Although there was no
change in glomerular eNOS monomer expression, both sepiapterin and L-arginine
partially reversed the defect in eNOS dimerization and phosphorylation. Hence,
our results support an important role for eNOS dysfunction in diabetes and
suggest that sepiapterin supplementation might have therapeutic potential in
diabetic nephropathy.

Investigators with authorship
Raymond HarrisVanderbilt University