Physiopathologie de la Néphropathie Diabétique

11

Physiopathologie de la Physiopathologie de la Néphropathie DiabétiqueNéphropathie Diabétique

Philippe RieuService de Néphrologie et de Transplantation

UMR CNRS 6198Reims

Development of diabetic nephropathyDevelopment of diabetic nephropathy

Diabetes (years)

0

40

80

120

160

5 10 15 20 25

GF

R (

ml/m

in)

2

4

6

8

10

12

14

I II III IV V

GFR

Pro

téin

uria

(g/

d)

5 years 15 years

55 1010 1515 2020 2525

Intermitentµalbuminuria

GMB thicknessmesangial expansion

Persistentµalbuminurie(30-300 µg/j)Hypertension

(15 %)

Glomerulosclerosis

Proteinuria(Nephrotic in 10 %)Hypertension (80 %)

Renal failure

MogensenMogensen DiabetesDiabetes 1983 32:641983 32:64

22

Marre M. et al. In Mogensen CE. The kidney and hype rtension in diabetes mellitus, chapter 35, third. B oston, Dordrecht, London : Kluwer Academic publishers 1997 : 351-60

Relation entre excrétion urinaire d’albumine et fil tration glomérulaire Relation entre excrétion urinaire d’albumine et fil tration glomérulaire chez des patients diabétiques de type 1 non traités par IEC.chez des patients diabétiques de type 1 non traités par IEC.

Development of diabetic nephropathyDevelopment of diabetic nephropathy

Diabetes (years)

0

40

80

120

160

5 10 15 20 25

GF

R (

ml/m

in)

2

4

6

8

10

12

14

I II III IV V

GFR

Pro

téin

uria

(g/

d)

5 years 15 years

55 1010 1515 2020 2525

Intermitentµalbuminuria

GMB thicknessmesangial expansion

Persistentµalbuminurie(30-300 µg/j)Hypertension

(15 %)

Glomerulosclerosis

4-15 ml/min/year

ESRD

MogensenMogensen DiabetesDiabetes 1983 32:641983 32:64

33

RAAS and RAAS and diabeticdiabetic nephropathynephropathy

Diabetes (years)

0

40

80

120

160

5 10 15 20 25

GF

R (

ml/m

in)

2

4

6

8

10

12

14

I II III IV V

Pro

téin

uria

(g/

d)

5 years 15 years

55 1010 1515 2020 2525

LewwisLewwis et al NEJM 1993 329:1456et al NEJM 1993 329:1456

CaptoprilCaptoprilPlaceboPlacebo

Lewis et al NEJM 1993 329:1456Lewis et al NEJM 1993 329:1456

Proportion of patients Proportion of patients withwith doublingdoubling of of basebase--line line creatininecreatinine

44


Diabetes (years)

0

40

80

120

160

5 10 15 20 25

GF

R (

ml/m

in)

2

4

6

8

10

12

14

I II III IV V

Pro

téin

uria

(g/

d)

5 years 15 years

55 1010 1515 2020 2525



Lewis et al NEJM 1993 329:1456Lewis et al NEJM 1993 329:1456VibertiViberti et al JAMA 1994 271: 275et al JAMA 1994 271: 275


Diabetes (years)

0

40

80

120

160

5 10 15 20 25

GF

R (

ml/m

in)

2

4

6

8

10

12

14

I II III IV V

Pro

téin

uria

(g/

d)

5 years 15 years

55 1010 1515 2020 2525


CandesartanCandesartanPlaceboPlacebo

LosartanLosartanEnalaprilEnalaprilPlaceboPlacebo


BilousBilous et al Ann et al Ann InternIntern Med 2009 151:11Med 2009 151:11Mauer et al NEJM 2009 361: 40Mauer et al NEJM 2009 361: 40

Lewis et al NEJM 1993 329:1456Lewis et al NEJM 1993 329:1456VibertiViberti et al JAMA 1994 271: 275et al JAMA 1994 271: 275

55

Proportion of patients Proportion of patients withwithmicroalbuminuriamicroalbuminuria

BilousBilous et al Ann et al Ann InternIntern Med 2009 151:11Med 2009 151:11

Proportion of patients Proportion of patients withwithmicroalbuminuriamicroalbuminuria

Mauer et al NEJM 2009 361: 40Mauer et al NEJM 2009 361: 40

66

HyperglycemiaHyperglycemiaDiabeticDiabetic tissuetissue

damagedamage

Risk of Diabetic tissue damageRisk of Diabetic tissue damage

7 9 11 13 15

Hemoglobin A1 (%)

0

2

4

6

8

10

12

Ris

k of

mic

roal

bum

inur

iaO

dds

ratio

A.S. Krolewski, N Eng J Med, 1995, 332:1251

Risk of Diabetic NephropathyRisk of Diabetic Nephropathy

77

A.R. Andersen, Diabetologia, 1983: 25:496

10 20 30 40

10

20

30

40

50

Duration of Diabetes (years)

Inci

denc

e of

Nep

hrop

athy

(%)

Risk of Diabetic NephropathyRisk of Diabetic Nephropathy

BloodBlood--glucose control and risk of glucose control and risk of diabetic tissue damagediabetic tissue damage

DCCTRG: 1441 type 1 DCCTRG: 1441 type 1 diabetesdiabetes patientspatients NEJM, 1993; 329:977NEJM, 1993; 329:977--986986

DiabeticDiabetic nephropathynephropathyBloodBlood--glucose controlglucose control

88

T0T0 T5T5 T10T10

Diabetic Nephropathy after pancreas Diabetic Nephropathy after pancreas transplantationtransplantation

Fioretto et al. NEJM 1998; 339:69


damagedamage

GeneticGenetic determinantsdeterminants ofofIndividualIndividual susceptibilitysusceptibility

IndependentIndependentaccelerating factorsaccelerating factors

(e.g. HTA, hyperlipemia…(e.g. HTA, hyperlipemia…


BrownleeBrownlee DiabetesDiabetes 2005, 54: 16152005, 54: 1615

99


damagedamage


HyperglycemiaHyperglycemiaHigh glucoseHigh glucoseInside the Inside the cellcell

DiabeticDiabetic tissuetissuedamagedamage


GlucoseGlucose GlucoseGlucose

GLUT1GLUT1

EndothelialEndothelial cellscellsMicrovascularMicrovascularcomplicationscomplications

DiabeticDiabeticnephropathynephropathyMesangialMesangial cellscells

1010

NormoglycemiaNormoglycemiaHigh glucoseHigh glucoseInside the Inside the cellcell


GlucoseGlucose

GlucoseGlucose

GLUT1GLUT1

DiabeticDiabeticGlomerulosclerosisGlomerulosclerosis

In vivoIn vivo

↑↑↑ ECM↑↑↑ ECMIn vitroIn vitro

OverexpressionOverexpression of GLUT1 in of GLUT1 in mesangialmesangial cellscells

HeiligHeilig et al JCI 1995 96:1802et al JCI 1995 96:1802Wang et al Am J Wang et al Am J PhysiolPhysiol RenalRenal 2010 2010





GLUT1GLUT1

1111


GLUT1GLUT1 G6PG6P

Fructose 6PFructose 6P

Fructose 1,6PFructose 1,6P

DihydroacetoneDihydroacetone PP

DiacylglycerideDiacylglyceride

3 P 3 P glyceraldehydeglyceraldehyde

PyruvatePyruvate MethylglyoxalMethylglyoxal

GlycolysisGlycolysis

TCA cycleTCA cycle


GLUT1GLUT1 G6PG6P

Fructose 6PFructose 6P

Fructose 1,6PFructose 1,6P

DihydroacetoneDihydroacetone PP

DiacylglycerideDiacylglyceride

3 P 3 P glyceraldehydeglyceraldehyde

PyruvatePyruvate

ROSROSPKCPKC

MethylglyoxalMethylglyoxal

AGEsAGEs


GlycolysisGlycolysis

TCA cycleTCA cycle

1212

HyperHyperglycemiaglycemia

GlucoseGlucose

GLUT1GLUT1PKCPKC

↓eNOS↓eNOS↑ET↑ET--11

↑VEGF↑VEGF ↑TGF ↑TGF ββ

↑ Collagen↑ Collagen↑ FN↑ FN

↑NF↑NF--κκBB ↑NAD(P)H↑NAD(P)Hoxydaseoxydase

LY333531LY333531Ruboxistaurin®Ruboxistaurin®

Meier et al, NDT 2007 22:2421Meier et al, NDT 2007 22:2421

Family of at least12 isotypes

GLUT1GLUT1



GlucoseGlucose

pyruvatepyruvate

1313

GLUT1GLUT1


ROSROS


↑ AGEs↑ AGEs ↑PKC↑PKC ↑NF↑NF--κκBB ↑ Angio↑ Angiotensinogentensinogen

GlucoseGlucose

↓eNOS↓eNOS↓ PC Synthase↓ PC Synthase

MolecularMolecular damagedamage SignalingSignaling effecteffect

GLUT1GLUT1

ROSROS


GlucoseGlucose

SOD1SOD1

AccelerationAcceleration of DNof DN PreventionPrevention of DNof DN

SOD TG SOD TG micemiceSOD KO SOD KO micemice

Craven et al. Diabetes 2001 50:2114DeRubertis et al. Diabetes 2004 53:762

DeRubertis et al. Metabolism 2007 56:1256

1414

GlucoseGlucose

GLUT1GLUT1AGEsAGEs

AGEsAGEs


Modification of Modification of intracellularintracellular proteinsproteins

TranscriptionTranscriptionfactorsfactors

ProteasomeProteasome

Queisser et al. Diabetes 2010 55:660Yao et al. J. Biol Chem 2007 282:31038

Early Early GlycosylationGlycosylation Products Products

NHNH22 NHNH

CHCH22

(CHOH)(CHOH)33

CHCH22OHOH

CC OO

Amadori ProductAmadori ProductSchiff BaseSchiff BaseProteinProteinGlucoseGlucose

++CC

OO

HH

(CHOH)(CHOH)33

CHCH22OHOH

CHOHCHOH

NHNH++

CCHH

(CHOH)(CHOH)33

CHCH22OHOH

CHOHCHOH

LysLys

1515

Amadori ProductAmadori Product

Schiff BaseSchiff Base

NHNH--ProteinProteinGlucoseGlucose ++


Advanced Glycation EndAdvanced Glycation End--ProductsProductsAGEsAGEs

OXIDATION Dehydratationcondensationfragmentationcyclisation ...


NHNH--ProteinProteinGlucoseGlucose ++

O2-

1616


Advanced Glycation EndAdvanced Glycation End--ProductsProductsAGEsAGEs

O2-

Dehydratationcondensationfragmentationcyclisation ...


NHNH--ProteinProteinGlucoseGlucose ++O2

-

Arabinose Glyoxal

O2-

NHNH--ProteinProtein

StressCarbonylé

CarboxymethyllysinePyrralinePentosidineGlyoxal-lysine-dimerMethyl-glyoxal-lysine-dimer

LysylpyrropyrineVesperlysineDehydrofuroimidazole

CrosslineImidazoloneGlucosepanCrosspy


1717

CarboxymethyllysinePyrralinePentosidineGlyoxal-lysine-dimerMethyl-glyoxal-lysine-dimer

LysylpyrropyrineVesperlysineDehydrofuroimidazole



Injection of AGE in normal rats

Glomerular hyperfiltrationGlomerular hypertrophy

GMB thickeningMesangial matrix expansion

Proteinuria

AGE and Diabetic NephropathyAGE and Diabetic Nephropathy

M. Sabbatini, Kidney int, 1992: 42:875H. Vlassara, Proc Natl Acad Sci USA, 1994, 91:11704

1818

Injection of AGE in normal rats



Proteinuria


M. Sabbatini, Kidney int, 1992: 42:875H. Vlassara, Proc Natl Acad Sci USA, 1994, 91:11704

Aminoguanidine

Diabetic rats



ProteinuriaAminoguanidineOBP-9195 Soulis et al; Diabetes, 1991, 40:1328

S. Nakamura, Diabetes, 1997, 46:895


1919

NHNH

AGEsAGEs

NHNH

NHNH

AGEsAGEs

Protein cross linkingProtein cross linking

NHNH

AGEsAGEs

RAGEAGE-R1 (P60/OST-48 protein)

AGE-R2 (80 K-H phosphoprotein)AGE-R3 (galectin-3)Scavenger receptor

AGE receptorsAGE receptors

2020

NHNH

NHNH

AGEsAGEs

NHNH

NHNH

AGEsAGEs

NHNH

NHNH

AGEsAGEs

Extracellular matrix proteinExtracellular matrix protein

NHNH

NHNH

AGEsAGEs

NHNH

NHNH

AGEsAGEs

CrossCross--linking oflinking ofECM proteinECM protein

Thickening of basement membrane and expansion of mesangial matrix

Cross-linking ofECM protein

Reduced susceptibility to proteolytic degradation

AGE

2121

Diabetic Nephropathy : Staining for AGEDiabetic Nephropathy : Staining for AGE

CMLCML

PentosidinePentosidine

NHNH

NHNH

AGEsAGEs

NHNH

NHNH

AGEsAGEs

NHNH

NHNH

AGEsAGEs

Extracellular matrix proteinExtracellular matrix protein

NHNH

NHNH

AGEsAGEs

NHNH

NHNH

AGEsAGEs

CrossCross--linking oflinking ofECM proteinECM protein

Trapping ofTrapping ofproteinprotein

2222

NHNH

AGEsAGEs

NHNH

NHNH

AGEsAGEs


NHNH

AGEsAGEs




NHNH

AGEsAGEs

NHNH

NHNH

AGEsAGEs


NHNH

AGEsAGEs




2323

Diabetic Nephropathy : Staining for RAGEDiabetic Nephropathy : Staining for RAGE

N. Tanji, J Am Soc Nephrol 2000 11:1656

Podocytes

VEGF

AGE

Cellular Activation

RAGE

Endothelial cells

Oxidant stressICAM-1, VCAM-1

VEGF, TNF Thromboxane

PAI-1, Tissue factor

Monocytes

VEGFPDGFTGFβ

2424

AGE

Cellular Activation

RAGE

Mesangials cells

TGFβType IV Collagen

FibronectinLaminin

Cohen et al, Am J Physiol, 1999, 276: F684Scivittaro et al, Am J Renal Physiol, 2000, 278:F67 6

Diabetic mice

Glomerular hypertrophyGMB thickening

Mesangial matrix expansionProteinuria

RAGE Tg+

RAGE and Diabetic NephropathyRAGE and Diabetic Nephropathy

Y.Yamamoto, J Clin Invest, 2001, 108:261

2525

Diabetic Nephropathy in Diabetic Nephropathy in RAGERAGE--overexpressing miceoverexpressing mice

Y.Yamamoto, J Clin Invest, 2001, 108:261

DM + RAGETg+

DM + RAGETg -

DM - RAGETg -

DM - RAGETg+

No difference inblood glucose, HbA1C,

AGE

Diabetic mice

Glomerular hypertrophyGMB thickening

Mesangial matrix expansionProteinuriasRAGE

Anti-RAGE

RAGE and Diabetic NephropathyRAGE and Diabetic Nephropathy

Wendt et al. AJP 2003 162: 1123Flyvbjerg et al, Diabetes 2004 53:166

2626

NHNH

AGEsAGEs

NHNH

AGEsAGEs

RAGERAGE

Cell activationCell activation

NHNH

AGEsAGEs

sRAGEsRAGE

Soluble RAGESoluble RAGE--treated diabetic micetreated diabetic mice

Wendt et al. AJP 2003 162: 1123

2727

Western BlotWestern Blot

antianti--RAGERAGE

NRK 52E CellsNRK 52E Cells

ImmunostainingImmunostaining

Human diabetic nephropathyHuman diabetic nephropathy

RAGE expression in tubulesRAGE expression in tubules

Oldfield et al, JCI, 2001 108:1853

NHNH

AGEsAGEs

RAGERAGE


TGF TGF ββ

NHNH

AGEsAGEs

RAGERAGE

TGF TGF ββ


EpithelialEpithelial--myofibroblast transdifferenciationmyofibroblast transdifferenciation

2828

AGEs induce EMT in vivoAGEs induce EMT in vivo

Oldfield et al, JCI, 2001 108:1853


DiabeticDiabeticnephropathynephropathy

Diabetic nephropathyDiabetic nephropathy


GLUT1GLUT1

GlucoseGlucoseCross-linking

of proteins

RAGE

AGE

AGE PKC ROS

↑EMC proteinsCell damage

Antioxydants

AGE inhibitors

Antidiabetic molecules Anti-RAGE

PKC inhibitors

Physiopathologie de la Néphropathie Diabétique

Documents

Transcript of Physiopathologie de la Néphropathie Diabétique