Programming of Renal Function before and after Birth · after IUGR Hyperalimentation 0 5 10 15 20...

Programming of Renal Function before and after

Birth

Jörg Dötsch

Perinatal Programming

Intrauterine milieue.g. lack of energy,

hypoxia

Postnatal phenotype i.e.

SGA

Morbidity later in life



hypoxia

Fetal ProgrammingPostnatal phenotype i.e.

SGA




hypoxia

Fetal Programming

Persistent changes due to programming


SGA


Birth weight and renal function (2,183,317 persons, born between 1967 and 2004 in Norway, 526 developed endstage renal failure)

(Vikse et al., JASN 2008)

Birth weight and renal function –Metaanalysis

(White et al., Am J Kidney Dis 2009)

Birth weight and kidney – Metaanalysis

(White et al., Am J Kidney Dis 2009)

Birth weight and renal function (Chronic Kidney Disease, DM or hypertension or first degree relative with DM or hypertension)

(Li et al., Kidney Int 2008)

N=2920

N=9444

In white man inverse J-shape!In Afroamerican man J-shape!

Birth weight and programming of renal function–questions


SGA = IUGR?


SGA = IUGR?

Causal relation IUGR – later morbidity ?


SGA = IUGR?


Prevention?


SGA = IUGR?


Prevention?

Mechanisms of disease?

SGA = IUGR ?

IUGR

Weeks of gestation

Birth

Weight

SGA = IUGR ?

IUGR

Weeks of gestation

Birth

Weight

Weeks of gestation

SGA

Birth

Weight

IUGR always SGA ?

IUGR

Weeks of gestation

Birth

Weight



hypoxia


SGA

Fetal Programming





hypoxia


SGA

Fetal Programming



Causal relation?

e.g. lack of enhypoxia


SGA

Persistent changprogramm

(Zidar et al., Nephron 1998)

SGA: Glomerulosclerosis in childhood IgA-Nephropathy

< 10. percentile > 10. Percentile0

25

50

75

Birth weight

Glo

mer

ulos

cler

osis

(%)

NP LP

IUGR in rats (low protein model)

(Plank et al., Kidney Int., 2006)

0 5 10 15 20 25

0

10

20

30

40

50

60

NPLP

Lebenstage

Kör

perg

ewic

ht (g

)w

eigh

t

Days of life

NP LP0

2

4

6

8 ***

bir th

wei

ght

IUGR + acute anti-Thy1.1-nephritis

IUGR

SFB423 TP13 (Plank et al., Kidney Int., 2006)

Control

IUGR: Acute Anti-Thy1.1-Nephritis / day 14Collagen (Immunohistochemistry)

SFB423 TP13 (Plank et al., Kidney Int., 2006)

IUGR +GN d27

Uterine artery ligation model: more severe course of anti-Thy1.1 Nephritis

SFB423 TP13(Nüsken et al., Endocrinology., 2008)

Uterine artery ligation model: more severe course of anti-Thy1.1 Nephritis

SFB423 TP13(Nüsken et al., Endocrinology., 2008)

UL Thy

1 (IU

GR)SHAM Thy

1UL P

BS (IUGR)

SHAM PBS

0

10

20 **C

olla

gen

I pos

itive

are

a pe

rG

lom

erul

um (%

)



hypoxia


SGA

Fetal Programming



Transient Enalapril Application afterIUGR before Anti-Thy1.1 Nephritis

SFB423 TP13


SFB423 TP13

IUGR

control

ACE-Inhibitor

Manning and Vehaskari, Hypertension 2001


SFB423 TP13

IUGR

control

ACE-Inhibitor

Manning and Vehaskari, Hypertension 2001

IUGR

control

+ Anti-Thy1 GN

d0 d58 d62d24 d42

Enalapril

Enalapril

IUGR

control

0

10

20

30 **

KontrolleIUGR

*

+Enal +Enal+Thy1+Thy1 +Thy1 +Thy1

Col

lage

n IV

pos

itive

are

ape

r Glo

mer

ulum

(%)

SFB423 TP13

Transient Enalapril Application after IUGR before Anti-Thy1.1 Nephritis

IUGR+T

HY1IU

GR+E+T

HY1co

ntrol+

THY1co

ntrol+

E+THY1

0

10

20cr

esce

nts

/100

glo

mer

uli

SFB423 TP13

Transient Enalapril Application after IUGR before Anti-Thy1.1 Nephritis

Blood pressure after Hyperalimentation in SGA-patients (age of measurements 6-8 years)

(Singal et al., Circulation, 2007)

Prevention of hyperalimentationafter IUGR

Hyperalimentation

0 5 10 15 20 25

0

10

20

30

40

50

60

NPLP

Lebenstage

Kör

perg

ewic

ht (g

)B

ody

wei

ght

Days of life

Prevention of hyperalimentationafter IUGR

Hyperalimentation

0 5 10 15 20 25

0

10

20

30

40

50

60

NPLP

Lebenstage

Kör

perg

ewic

ht (g

)B

ody

wei

ght

Days of life

No hyperalimentation

0 5 10 15 20 2505

101520253035404550556065

NP (10 rats)LP (10 rats)

Tag

Kör

perg

ewic

ht (g

)B

ody

wei

ght

Days of life

HA-IUGR

HA-nonIUGR

nonHA-IUGR

nonHA-nonIUGR

012345678 ***re

l. IL

6 m

RN

A E

xpre

ssio

n

Renal Inflammation after Prevention of Hyperalimentation (HA), day 70

SFB423 TP13 (Plank et al., submitted)

Glomerulosclerosis after Prevention of Hyperalimentation (HA), day 70

HA-IUGR

HA-nonIUGR

non-HA-IUGR

non-HA-nonIUGR

0.0

0.1

0.2

0.3

0.4

0.5

****

***G

lom

erul

oscl

eros

is S

core


Albumine Excretion after Prevention of Hyperalimentation (HA), day 70, male animals

HA-IUGR

HA-nonIUGR

nonHA-IUGR

nonHA-nonIUGR

0

25

50

75

100

125 *A

lbum

ine

Excr

etio

n (µ

g/m

g K

rea)


Albumine Excretion after Prevention of Hyperalimentation (HA), day 360

(Boubred et al., Am J Physiol Renal Physiol, 2009)

nonI

UG

R

IUG

R

HA

-non

IUG

R

HA

-IUG

R

nonI

UG

R

IUG

R

HA

-non

IUG

R

HA

-IUG

R

10 animals (WR10)

6 animals (WR6)

16 – 18 animals (Co)

gestation

birth weaning

lactation

conception

day 0 P 23P 1 P 70

sacrifice,

metabolic cageEarly postnatal period

Postnatal hyperalimentation only

SFB423 TP13

Geburt 1 2 30

5

10

15

20

25

30

35

40

45

50

55

60

65WR 10WR 6

*

***

Lebenswoche

Kör

perg

ewic

ht (g

)Outcome after postnatal hyperalimentation

body weight (g)

birth

SFB423 TP13

Co WR10 WR6

Coll I glomerularColl I glomerular

0123456789

101112

*C

olla

gen

I pos

itive

are

a pe

rin

ters

titie

ll cr

oss-

sect

ion

(%)

Coll I interstitiellColl I interstitiell

Co WR10 WR6

Geburt 1 2 30

5

10

15

20

25

30

35

40

45

50

55

60

65WR 10WR 6

*

***

Lebenswoche

Kör

perg

ewic

ht (g

)Outcome after postnatal hyperalimentation

body weight (g)

birth

SFB423 TP13

0123456789

101112

*

Col

lage

n I p

ositi

ve a

rea

per

glom

erul

ar c

ross

-sec

tion

(%)

Co WR10 WR6

Coll I glomerularColl I glomerular

0123456789

101112

*C

olla

gen

I pos

itive

are

a pe

rin

ters

titie

ll cr

oss-

sect

ion

(%)

Coll I interstitiellColl I interstitiell

Co WR10 WR6

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

*m

RN

A fo

ld in

duct

ion

0

1

2

3

4 *

mR

NA

fold

indu

ctio

n

0

1

2

3

4

5

6 *

mR

NA

fold

indu

ctio

n

IL-10MCP-1 PAI-1

Co WR10 WR6 Co WR10 WR6 Co WR10 WR6

0

20000

40000

60000

80000 ***

Alb

um

in i

m U

rin

(n

g\m

l)

Albuminuria (g/g Crea (P120)Albuminuria (g/g Crea (P120)

WR10 WR6

FeK

0

10

20

30

40

50

60

70

**

FeK

(%)

Co WR10 WR6

Outcome after postnatal hyperalimentation

0

10

20

30

40

50

*

IL-6

mR

NA

fold

indu

ctio

n

IL-6 expression

Co WR10 WR6

Role of NPY?

SFB423 TP13

0.0

2.5

5.0

7.5

10.0 **

IL6/

ßA

ctin

Co WR10 WR6

0

10

20

30

40

50

*

IL-6

mR

NA

fold

indu

ctio

n

IL-6 expression

Co WR10 WR6

Role of NPY?

SFB423 TP13

IL-6

ß-Act

Co WR10 WR6

0.0

2.5

5.0

7.5

10.0 **

IL6/

ßA

ctin

Co WR10 WR6

0

10

20

30

40

50

*

IL-6

mR

NA

fold

indu

ctio

n

IL-6 expression

Co WR10 WR6

Role of NPY?

SFB423 TP13

IL-6

ß-Act

Co WR10 WR6

0

5

10

15 *

NP

Y m

RN

A f

old

indu

ctio

n

NPY expression

Co WR10 WR6

0.0

2.5

5.0

7.5

10.0 **

IL6/

ßA

ctin

Co WR10 WR6



hypoxia


SGA

Fetal Programming





hypoxia


SGA

Fetal Programming



WhatMechanisms?

Nephrogene Zone

NP LP 100

125

150

175

200

***

µm

Proliferating Cell Nuclear Antigen (PCNA)

*

Low protein model, P1

Nephrogenic zone in IUGR animals

Nephron number after Prevention of Hyperalimentation (HA), day 70


HA-IUGR

HA-non-IUGR

nonHA-IUGR

nonHA-nonIUGR

0

10000

20000

30000

40000

50000

60000

70000

***

**

glom

erul

i per

kid

ney

Renin - kidney AT1b-R - adrenal

Renin and AT1b after intrauterine growth restriction (Clear: control, black: IUGR)

(Bogdarina et al., Circ Res, 2007)

Methylation of AT1b-Promotor CpG-sites

Control - IUGRControl - IUGR

(Bogdarina et al., Circ Res, 2007)

PlacentaMother Fetus

11β-HSD 2Adequate placentafunction

Cortisol Cortisol

Gluco-/MineralocorticoidReceptor

11β-HSD 2 ↓Placenta-insufficieny

Cortisol Cortisol



Cortisol Cortisol



Cortisol Cortisol

-Growthrestriction

-Modification ofneuroendocrinedevelopment

11β-HSD 2 downregulated in IUGR placentae

IUGR control0

10

20

30 ***11β -

HSD

2/β -

actin

(rel

ativ

e un

its)

(Struwe et al., Am. J. Obstet. Gynecol, 2007)

11β-HSD2 expression in placenta in relation to birth weight

-6 -5 -4 -3 -2 -1 00

1

2

r=0.58p=0.02

Birth length SDS

11ßH

SD2/

ß2M

G m

RN

A(r

elat

ive

units

)

(Tschoppe et al., Ped.Res., 2009)

11β-HSD2 Expression in Placenta is related to catch-up growth in IUGR-infants

(Tschoppe et al., Ped.Res., 2009)

20 25 30 35 400

1

2

r=-0.61p=0.01

Growth velocity (cm/year)

11ßH

SD2/

ß2M

G m

RN

A(r

elat

ive

units

)

-Growthrestriction



Cortisol Cortisol



Cortisol Cortisol


-Growthrestriction



Cortisol Cortisol



Cortisol Cortisol


-Postnatalchange inCortisolmetabolism

(Bertam et al. Endocrinology, 2001)

IUGR in rats: 11β-HSD2 Gene Expression in Entire Kidney Tissue

(Östreicher et al., NDT in revision)

IUGR in rats (low-protein): 11β-HSD2Immunohistochemistry and Gene Expression

control IUGR

control IUGR

(Östreicher et al., NDT in revision)

IUGR in rats (low-protein): 11β-HSD2Immunohistochemistry and Gene Expression

control IUGR

control IUGR

Control IUGR0.00

0.25

0.50

0.75

1.00

1.25

rel.

fold

mR

NA

exp

ress

ion

11ßHSD2

*Microdissected tubuli

endothelial cell

vascular smooth muscle cellcGMP ↓

Vasodilatation ↓

acetylcholine/flow-mediated

NOS ↓

ET-1 ↑

BH4 ↓

NO ↓ O2• ↑AT1b-R ↑

phenylephrine

Vasoconstriction ↑

α1 ↑

Control IUGR0

1

2

3

4p<0.001

Rel

ativ

e In

crea

se in

rena

lEn

doth

elin

-1 E

xpre

ssio

n

Renal endothelin-1 upregulation after intrauterine growth restriction

SFB423 TP13

Renal dysfunction

Sympathetic nerve activity

Reduced activity of 11β hydroxysteroid dehydrogenase

Reduced nephron number

Increased activity of RAAS

Pathological endothelial/ smooth muscle function

Altered vascular structure

Renal Factors

Extrarenal Factors

Adverse intrauterineenvironment

Epigeneticfactors

Epigeneticfactors


SGA ≠ IUGR


SGA ≠ IUGR


→ animal experiments (different models)


SGA ≠ IUGR



Prevention ?

→ avoiding hyperalimentation?


SGA ≠ IUGR



Prevention ?

→ avoiding hyperalimentation?

Mechanisms ?

→ extrarenal (e.g. endothelium, sympathetic nerve system)

→ renal (e.g. nephron number, RAAS, 11ß-HSD)

AcknowledgementsIda Allabauer Prof. Dr. Amann, Erlangen

Ivonne Birkner Prof. Dr. Hilgers , Erlangen

Julia Dobner

Katrin Schmied

Dr. Miguel Alcazar

Dr. Fabian Fahlbusch FIPS-Study Group

PD Dr. Andrea Hartner (ER, F, HAL, K, J)

Dr. Carlos Menendez

Dr. Kai Nüsken

Dr. Iris Östreicher

Dr. Christian Plank DFG DO 682/3-3

PD Dr. Ellen Struwe SFB 423, TP B13

Dr. Anja Tzschoppe

Programming of Renal Function before and after Birth · after IUGR Hyperalimentation 0 5 10 15 20...

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