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Enhanced Renal Afferent Arteriolar Reactive Oxygen Species and Contractility to
Endothelin-1 Are Associated with Canonical Wnt Signaling in Diabetic Mice
#MMPMID29870994
Zhang S
; Huang Q
; Wang Q
; Wang Q
; Cao X
; Zhao L
; Xu N
; Zhuge Z
; Mao J
; Fu X
; Liu R
; Wilcox CS
; Patzak A
; Li L
; Lai EY
Kidney Blood Press Res
2018[]; 43
(3
): 860-871
PMID29870994
show ga
BACKGROUND/AIMS: Canonical Wnt signaling is involved in oxidative stress,
vasculopathy and diabetes mellitus but its role in diabetic renal microvascular
dysfunction is unclear. We tested the hypothesis that enhanced canonical Wnt
signaling in renal afferent arterioles from diabetic mice increases reactive
oxygen species (ROS) and contractions to endothelin-1 (ET-1). METHODS:
Streptozotocin-induced diabetes or control C57Bl/6 mice received vehicle or
sulindac (40 mg·kg-1·day-1) to block Wnt signaling for 4 weeks. ET-1 contractions
were measured by changes of afferent arteriolar diameter. Arteriolar H2O2, O2 -,
protein expression and enzymatic activity were assessed using sensitive
fluorescence probes, immunoblotting and colorimetric assay separately. RESULTS:
Compared to control, diabetic mouse afferent arteriole had increased O2- (+ 84%)
and H2O2 (+ 91%) and enhanced responses to ET-1 at 10-8 mol·l-1 (-72±4% of versus
-43±4%, P< 0.05) accompanied by reduced protein expressions and activities for
catalase and superoxide dismutase 2 (SOD2). Arteriolar O2 - was increased further
by ET-1 and contractions to ET-1 reduced by PEG-SOD in both groups whereas H2O2
unchanged by ET-1 and contractions were reduced by PEG-catalase selectively in
diabetic mice. The Wnt signaling protein ?-catenin was upregulated (3.3-fold
decrease in p-?-catenin/?-catenin) while the glycogen synthase kinase-3? (GSK-3?)
was downregulated (2.6-fold increase in p-GSK-3?/ GSK-3?) in preglomerular
vessels of diabetic mice. Sulindac normalized the Wnt signaling proteins,
arteriolar O2 -, H2O2 and ET-1 contractions while doubling microvascular catalase
and SOD2 expression in diabetic mice. CONCLUSION: Increased ROS, notably H2O2
contributes to enhanced afferent arteriolar responses to ET-1 in diabetes, which
is closely associated with Wnt signaling. Antioxidant pharmacological strategies
targeting Wnt signaling may improve vascular function in diabetic nephropathy.
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