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Roderick TanLab of Youhua Liu
Departments of Medicine and PathologyOctober 24, 2013
EXTRACELLULAR SUPEROXIDE DISMUTASE IN KIDNEY DISEASE
OUTLINE• Oxidative Stress in Renal Fibrosis
• Introduction to EC-SOD
• Role of EC-SOD in Adriamycin Injury
• Association with Wnt/beta-catenin signaling
OXIDATIVE STRESS (OS)
ROS
AntioxidantsInflammationAngiotensin IINADPH oxidases
SOD, Catalase,Glutathione peroxidase
EXTRACELLULAR SUPEROXIDE DISMUTASE (EC-SOD)
• 1 of 3 isoforms of SOD
• Antioxidant enzyme
• High expression in normal kidney
Folz et al., AJRCMB 1997
O2- + O2
- O2 + H2O2
2H+
EC-SOD
K ~ 1 x 109
Molecular Oxygen (O2)Superoxide (O2-)
O O׃ ׃ ׃׃ ׃
● ● ●
O = O׃׃׃׃
-
Inflammatory CellsActivated Fibroblasts, Epithelium, Endothelium
O2●-
EC-SOD prevents superoxide from forming potent reactive oxygen species
+ NO●ONOO- HO●
NO2
Fe3+Fe2+
H202
HO●
EC-SODCell and tissue damage, signaling cascades, aging,etc.
ADRIAMYCIN NEPHROPATHY• Murine model for FSGS• Single IV (tail vein) injection• Glomerular injury proteinuria• Tubular damage / fibrosis• Superoxide-mediated
ADR INJURY IN WILD TYPE MICE
CTL ADR0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
CTL ADR0
25
50
75
100
125
seru
m c
reat
inin
e (m
g/d
L)
mg
Ual
b /
mg
UC
r* *
EC-SOD KO MICE ARE SENSTIVIE TO ADR INJURY
WT ADR KO ADRD
HE
WT KO0
5000
10000
15000
20000
25000
Th
resh
old
ed
are
a
*
NADPH OXIDASE
WT KO0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
NO
X2
WT KO0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
NO
X4
*
EC-SOD KO MICE ARE SENSTIVIE TO ADR INJURY
TIME 0
4 WK 5 WK 6 WK 7 WK 8 WK0
50
100
150
200
250
300
350
400
450
WILD TYPE ECSOD KO
mg
Ua
lb /
mg
UC
r
**
*
*
*
*
EC-SOD KO MICE ARE SENSITIVE TO ADR INJURY
WT KO0.0
0.5
1.0
1.5
2.0
2.5
fib
ron
ec
tin
mR
NA
WT KO0.0
0.2
0.4
0.6
0.8
de
sm
in
WT KO0.0
1.0
2.0
3.0
4.0
fib
ron
ecti
n **
*
WNT/BETA-CATENIN SIGNALING
• Developmental pathway
• Quiescent in normal adult kidney tissue
• Upregulated in glomerular and interstitial injuries
• Blockade ameliorates of renal injury
He, JASN (2009, 2011); Hao, JASN (2011); Dai, JASN (2009)
EC-SOD KO MICE ARE SENSTIVIE TO ADR INJURY
WT KO
β-c
aten
in
WT ADR KO ADR0.00
1.00
2.00
3.00
4.00
MM
P-7
mR
NA *
SUMMARY
• EC-SOD is depleted from kidneys after ADR
• EC-SOD KO mice are sensitized to oxidative stress, proteinuria and fibrosis after ADR
• EC-SOD KO have increased b-catenin activation after ADR
MODEL OF INJURYADRIAMYCIN
PODOCYTE / GLOMERULAR INJURY
PROTEINURIA
FIBROSISDECREASED RENAL FUNCTION
EC-SOD
ACKNOWLEDGMENTS• Liu Lab
• Youhua Liu
• Dong Zhou
• Liangxiang Xiao
• Lin Lin
• Tom Kleyman
• Tim Oury
• Donna Beer-Stolz
• Bruce Freeman
• Ken Hallows
• Pittsburgh Center for Kidney Research
• Center for Biologic Imaging
• NIDDK R01 DK091239
• NIDDK T32 DK061296
• AHA FTF 16990086