ros as targets for therapeutic intervention of diabetic ... · 36 th autumn congress of korean...

36th Autumn Congress of Korean Diabetes AssociationSeptember 16-17 2010 BEXCO Busan Korea

ROS as targets for therapeutic intervention of diabetic nephropathy

Hunjoo Ha

Department of Bioinspired ScienceDivision of Life amp Pharmaceutical Sciences

College of Pharmacy Ewha Womans University Seoul Korea

Definition of the term ROS (reactive oxygen species) and OS (oxidative stress)

Current understanding of ROS-induced renal injury under hyperglycemia

Contents

renal injury under hyperglycemiaRole of antioxidant defense mechanism

under hyperglycemia catalase Nrf2 Recent therapeutic advances supporting

the role of ROS in diabetic renal injury

O2 O2- H2O2 OH + OH- 2H2O

e e e e

4e

Sequential reduction of O2

O2-

Weak oxidant acting on Fe-S Fe-Zn centersH2O2 Weak oxidant oxidizing sulfur atoms of Cys and Met

OH Strong oxidant indiscriminately damaging DNA Proteins Lipids

O2 2H2O4e

+ 4H+

HO O

H

Finkel T et al Nature 408239 2000

O2-

H2O2

OH

Oxidative Stress

SODGPxcatalaseAntioxidantDefense

MechanismsROS



Role of antioxidant defense mechanism Role of antioxidant defense mechanism under hyperglycemia catalase Nrf2

Recent therapeutic advances supporting the role of ROS in diabetic renal injury

Increased ROS under hyperglycemia

Koya D et al JASN 14S250 2003Ha H et al JASN 3894 2002 Unpublished data

Markers of OS in human DN

GFAT

protein

PKC

ROS-regulated signaling in renal cells under hyperglycemia

Lee HB et al JASN 14S241-5 2003





A heme-containing homotetrameric protein Mainly located in the peroxisomes

H2O2 O2 + 2H2O

OH- + OH

Catalase

Fe (Ⅱ)Fenton reaction

Role of catalase in diabetic nephropathy

Fenton reaction

Ho et al JBC 27932804 2004

Characteristics of diabetic cat null mice

04050607

(mgd

L)

C

10

15

20

25

D

Pla

sm

a F

FA (m

M) dagger

B

Rela

tive

incre

ase

3456

daggersect

A

n=7~8 Mean plusmn SE plt005 vs WT dagger plt005 vs Cat-- sect plt005 vs WT+DM

Unpublished data

00102030405

PC

r (m

gd

L)

00

05

10

Pla

sm

a F

FA (m

M)

Rela

tive

incre

ase

0123

WT

WT+

DM

Cat

--

Cat

--+

DM

Cat --

WT Cat --+DMWT+DM

0

05

1

15

WT WT+DM Cat-- Cat--+DM

Relative increase

Glomerular volume

Fractional mesangial area

daggersect

Glomerular volume amp FMA in diabetic cat null mice

WT

Unpublished data

05

07

09


FMA

Fractional mesangial area (FMA)

Cat--

con DM


Renal injury in diabetic cat null mice

00 05 10 15 20 25 30 35

TGF-

β1

18S

daggersect

A

00 05 10 15 20 25 30 35 40 45

CTG

F18

S

daggersect

B

00 05 10 15 20 25 30 35 40 45 50

BM

P7

18S

dagger

C

0

50

100

150

200

250

300

daggersect

BM

P7

(pgm

g p

rote

in)D

Unpublished data


WT Cat-- Cat--+DM

D

BM

P7

(pgm

g p

rote

in)

WT+DM

Oxidative stress in diabetic cat null mice

00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM

plt005 vs WT dagger plt005 vs Cat--

00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE

Diabetic renal injury in Nrf2 null mice

Role of ROS in HG-induced Nrf2 activation

NAC





Dose of antioxidants Concentration of antioxidants at the site of ROS produced (eg mitochondria) Plasma half-life of antioxidants

Successful antioxidant therapy will depend onhellip

Plasma half-life of antioxidants Safety and tolerability of antioxidants Type of antioxidants antioxidants may act as oxidants Oxidative state of patients

Bardoxolone methyl an inducer of Nrf2

Phase IIa trialRenoprotective effect of bardoxolone methyl on diabetes

Selective mitochondrial antioxidants MitoQ

Permeable into mitochondria 100~1000 fold accumulation

Adsorbed to the matrix surface of inner membrane Accumulated in the heart liver skeletal muscle kidney and brain

Oral bioavailability 10 Major metabolites in the urine glucuronide amp sulfate conjugation

PROTECT study Parkinsonrsquos diseasebull Double-blind studybull 40 80 mgkg for 12 months

Human studies with MitoQ

bull 40 80 mgkg for 12 months CLEAR trial chronic HCV unresponsive to conventional txbull Double-blind randomized studybull 0 40 80 mgkg for 28 days

Common adverse effect dose-dependent nausea

httpwwwantipodeanpharmacom

Haptoglobin (Hp) genotype amp DN

a hemoglobin binding protein protects against heme-induced ROS 3 genotypes Hp 1-1 Hp 2-2 and Hp 2-1 Diabetes with Hp 2-2 have 2~5 fold increasedrisk of CVD

Increased generation of ROS in diabetic kidney is convincing Endogenous antioxidant defense mechanism plays a protective role in DN

Antioxidants acting directly at the mitochondrial site may

Conclusion

Antioxidants acting directly at the mitochondrial site may promise better efficiency than non-specific antioxidants

Pharmacogenomic application may provide a rational for prospective trials to investigate the potential of vigorous antioxidant therapy to ameliorate DN

Body wt (g)

Kidney wtbody wt (ratio)

Blood glucose (mgdL)

Plasma creatinine (mgdL)

UAE(mg24 hrs)

WT 228 plusmn 07 743 plusmn 008 193 plusmn 15 138 plusmn 027 060 plusmn 028

WT+DM 190 09 756 019 362 50 119 026 150 046


WT+DM 190 plusmn 09 756 plusmn 019 362 plusmn 50 119 plusmn 026 150 plusmn 046

Cat-- 275 plusmn 05 722 plusmn 006 175 plusmn 17 144 plusmn 025 048 plusmn 017

Cat--+DM 231 plusmn 09daggersect 784 plusmn 010dagger 397 plusmn 74dagger 114 plusmn 021 724 plusmn 265daggersect

n=7~8 Mean plusmn SE plt005 vs WTdagger plt005 vs Cat-- sect plt005 vs WT+DMUAE urinary albumin excretion

Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J

Unpublished datan=7~8 Mean plusmn SE plt005 vs WT dagger plt005 vs Cat--

0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data

n=7~8 Mean plusmn SE plt005 vs WT dagger plt005 vs Cat--

00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e





Contents

renal injury under hyperglycemiaRole of antioxidant defense mechanism

under hyperglycemia catalase Nrf2 Recent therapeutic advances supporting

the role of ROS in diabetic renal injury


e e e e

4e


O2-



O2 2H2O4e

+ 4H+

HO O

H


O2-

H2O2

OH

Oxidative Stress


MechanismsROS








GFAT

protein

PKC








H2O2 O2 + 2H2O

OH- + OH

Catalase



Fenton reaction

Ho et al JBC 27932804 2004


04050607

(mgd

L)

C

10

15

20

25

D

Pla

sm

a F

FA (m

M) dagger

B

Rela

tive

incre

ase

3456

daggersect

A


Unpublished data

00102030405

PC

r (m

gd

L)

00

05

10

Pla

sm

a F

FA (m

M)

Rela

tive

incre

ase

0123

WT

WT+

DM

Cat

--

Cat

--+

DM

Cat --

WT Cat --+DMWT+DM

0

05

1

15


Relative increase

Glomerular volume


daggersect


WT

Unpublished data

05

07

09


FMA


Cat--

con DM



00 05 10 15 20 25 30 35

TGF-

β1

18S

daggersect

A

00 05 10 15 20 25 30 35 40 45

CTG

F18

S

daggersect

B

00 05 10 15 20 25 30 35 40 45 50

BM

P7

18S

dagger

C

0

50

100

150

200

250

300

daggersect

BM

P7

(pgm

g p

rote

in)D

Unpublished data


WT Cat-- Cat--+DM

D

BM

P7

(pgm

g p

rote

in)

WT+DM


00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM


00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e




e e e e

4e


O2-



O2 2H2O4e

+ 4H+

HO O

H


O2-

H2O2

OH

Oxidative Stress


MechanismsROS








GFAT

protein

PKC








H2O2 O2 + 2H2O

OH- + OH

Catalase



Fenton reaction

Ho et al JBC 27932804 2004


04050607

(mgd

L)

C

10

15

20

25

D

Pla

sm

a F

FA (m

M) dagger

B

Rela

tive

incre

ase

3456

daggersect

A


Unpublished data

00102030405

PC

r (m

gd

L)

00

05

10

Pla

sm

a F

FA (m

M)

Rela

tive

incre

ase

0123

WT

WT+

DM

Cat

--

Cat

--+

DM

Cat --

WT Cat --+DMWT+DM

0

05

1

15


Relative increase

Glomerular volume


daggersect


WT

Unpublished data

05

07

09


FMA


Cat--

con DM



00 05 10 15 20 25 30 35

TGF-

β1

18S

daggersect

A

00 05 10 15 20 25 30 35 40 45

CTG

F18

S

daggersect

B

00 05 10 15 20 25 30 35 40 45 50

BM

P7

18S

dagger

C

0

50

100

150

200

250

300

daggersect

BM

P7

(pgm

g p

rote

in)D

Unpublished data


WT Cat-- Cat--+DM

D

BM

P7

(pgm

g p

rote

in)

WT+DM


00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM


00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e




O2-

H2O2

OH

Oxidative Stress


MechanismsROS








GFAT

protein

PKC








H2O2 O2 + 2H2O

OH- + OH

Catalase



Fenton reaction

Ho et al JBC 27932804 2004


04050607

(mgd

L)

C

10

15

20

25

D

Pla

sm

a F

FA (m

M) dagger

B

Rela

tive

incre

ase

3456

daggersect

A


Unpublished data

00102030405

PC

r (m

gd

L)

00

05

10

Pla

sm

a F

FA (m

M)

Rela

tive

incre

ase

0123

WT

WT+

DM

Cat

--

Cat

--+

DM

Cat --

WT Cat --+DMWT+DM

0

05

1

15


Relative increase

Glomerular volume


daggersect


WT

Unpublished data

05

07

09


FMA


Cat--

con DM



00 05 10 15 20 25 30 35

TGF-

β1

18S

daggersect

A

00 05 10 15 20 25 30 35 40 45

CTG

F18

S

daggersect

B

00 05 10 15 20 25 30 35 40 45 50

BM

P7

18S

dagger

C

0

50

100

150

200

250

300

daggersect

BM

P7

(pgm

g p

rote

in)D

Unpublished data


WT Cat-- Cat--+DM

D

BM

P7

(pgm

g p

rote

in)

WT+DM


00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM


00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e










GFAT

protein

PKC








H2O2 O2 + 2H2O

OH- + OH

Catalase



Fenton reaction

Ho et al JBC 27932804 2004


04050607

(mgd

L)

C

10

15

20

25

D

Pla

sm

a F

FA (m

M) dagger

B

Rela

tive

incre

ase

3456

daggersect

A


Unpublished data

00102030405

PC

r (m

gd

L)

00

05

10

Pla

sm

a F

FA (m

M)

Rela

tive

incre

ase

0123

WT

WT+

DM

Cat

--

Cat

--+

DM

Cat --

WT Cat --+DMWT+DM

0

05

1

15


Relative increase

Glomerular volume


daggersect


WT

Unpublished data

05

07

09


FMA


Cat--

con DM



00 05 10 15 20 25 30 35

TGF-

β1

18S

daggersect

A

00 05 10 15 20 25 30 35 40 45

CTG

F18

S

daggersect

B

00 05 10 15 20 25 30 35 40 45 50

BM

P7

18S

dagger

C

0

50

100

150

200

250

300

daggersect

BM

P7

(pgm

g p

rote

in)D

Unpublished data


WT Cat-- Cat--+DM

D

BM

P7

(pgm

g p

rote

in)

WT+DM


00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM


00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e








H2O2 O2 + 2H2O

OH- + OH

Catalase



Fenton reaction

Ho et al JBC 27932804 2004


04050607

(mgd

L)

C

10

15

20

25

D

Pla

sm

a F

FA (m

M) dagger

B

Rela

tive

incre

ase

3456

daggersect

A


Unpublished data

00102030405

PC

r (m

gd

L)

00

05

10

Pla

sm

a F

FA (m

M)

Rela

tive

incre

ase

0123

WT

WT+

DM

Cat

--

Cat

--+

DM

Cat --

WT Cat --+DMWT+DM

0

05

1

15


Relative increase

Glomerular volume


daggersect


WT

Unpublished data

05

07

09


FMA


Cat--

con DM



00 05 10 15 20 25 30 35

TGF-

β1

18S

daggersect

A

00 05 10 15 20 25 30 35 40 45

CTG

F18

S

daggersect

B

00 05 10 15 20 25 30 35 40 45 50

BM

P7

18S

dagger

C

0

50

100

150

200

250

300

daggersect

BM

P7

(pgm

g p

rote

in)D

Unpublished data


WT Cat-- Cat--+DM

D

BM

P7

(pgm

g p

rote

in)

WT+DM


00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM


00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e




04050607

(mgd

L)

C

10

15

20

25

D

Pla

sm

a F

FA (m

M) dagger

B

Rela

tive

incre

ase

3456

daggersect

A


Unpublished data

00102030405

PC

r (m

gd

L)

00

05

10

Pla

sm

a F

FA (m

M)

Rela

tive

incre

ase

0123

WT

WT+

DM

Cat

--

Cat

--+

DM

Cat --

WT Cat --+DMWT+DM

0

05

1

15


Relative increase

Glomerular volume


daggersect


WT

Unpublished data

05

07

09


FMA


Cat--

con DM



00 05 10 15 20 25 30 35

TGF-

β1

18S

daggersect

A

00 05 10 15 20 25 30 35 40 45

CTG

F18

S

daggersect

B

00 05 10 15 20 25 30 35 40 45 50

BM

P7

18S

dagger

C

0

50

100

150

200

250

300

daggersect

BM

P7

(pgm

g p

rote

in)D

Unpublished data


WT Cat-- Cat--+DM

D

BM

P7

(pgm

g p

rote

in)

WT+DM


00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM


00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e



0

05

1

15


Relative increase

Glomerular volume


daggersect


WT

Unpublished data

05

07

09


FMA


Cat--

con DM



00 05 10 15 20 25 30 35

TGF-

β1

18S

daggersect

A

00 05 10 15 20 25 30 35 40 45

CTG

F18

S

daggersect

B

00 05 10 15 20 25 30 35 40 45 50

BM

P7

18S

dagger

C

0

50

100

150

200

250

300

daggersect

BM

P7

(pgm

g p

rote

in)D

Unpublished data


WT Cat-- Cat--+DM

D

BM

P7

(pgm

g p

rote

in)

WT+DM


00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM


00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e




00 05 10 15 20 25 30 35

TGF-

β1

18S

daggersect

A

00 05 10 15 20 25 30 35 40 45

CTG

F18

S

daggersect

B

00 05 10 15 20 25 30 35 40 45 50

BM

P7

18S

dagger

C

0

50

100

150

200

250

300

daggersect

BM

P7

(pgm

g p

rote

in)D

Unpublished data


WT Cat-- Cat--+DM

D

BM

P7

(pgm

g p

rote

in)

WT+DM


00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM


00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e




00

05

10

15

20

25

Nox4

18S

+

08

10

12

18S

WT

WT+

DM


00

03

05

08

10

13

15

SOD

218

S

00

02

04

06

08

Cat

alas

e18

S

WT+

DM

Cat

--

Cat

--D

M

Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e



Nrf2-Keap1-ARE



NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e





NAC























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e

























Conclusion



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e



Body wt (g)




UAE(mg24 hrs)


WT+DM 190 09 756 019 362 50 119 026 150 046






Unpublished data


00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e




00 05 10 15 20 25

αSM

A1

8Sdaggersect

E

4

5

6

18S

G

E-cadherin

β-actin

α-SMA

Contr

ol

DM

Contr

ol

DM

WT Cat --

H

00

05

10

15

20

25

αSM

Aβ

-act

inI

20

25

cadher

in

actin

J


0

1

2

3

4

E-ca

dher

in1

8S

dagger

WT Cat

00

05

10

15

20

dagger

E-ca

dher

inβ-a

ctin

WT Cat-- Cat--+DM

D

WT+DM


10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e




10

15

20

25

Nox4

18S

+

05

08

10

13

15

SOD

218

S

04

06

08

10

12

Cat

alas

e18

S

Unpublished data


00

05 Nox4

18S

00

03 SOD

218

S

00

02

04

Cat

alas

e



ros as targets for therapeutic intervention of diabetic ... · 36 th autumn congress of korean...

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