M.Schreuder has documented that he has no relevant ... has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve. ... NCP Nephrol

M.Schreuder has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.

Role of epigenetics in the development of CAKUT

Michiel SchreuderPediatric Nephrologist4 September 2015

Epigenetics in CAKUT

• Kidney development

• CAKUT

• Epigenetics

• Epigenetics in CAKUT

• Conclusion

Kidney development

Nephrogenesis – Branching morphogenesis

Cell Cycle 2006;13:1426

Nephrogenesis

J Ped Surg 1982;17:728

CAKUT

CongenitalAnomalies of theKidney andUrinaryTract

NCP Nephrol 2008;4:312

Causes of CAKUT – Nature

Causes of CAKUT – Nature + Nurture

Developmental

Origins of Health

and Disease

(DOHaD)

Barker hypothesis

Perinatal

programming

Causes of CAKUT – Nature + Nurture

Causes of CAKUT – Epigenetics

Epigenetics – a definition

“The term epigenetics refers to

heritable changes in gene expression

(active versus inactive genes) that

does not involve changes to the underlying DNA

sequence;

a change in phenotype without a change in

genotype.”

Epigenetics – an example

Epigenetics – an example

• Temperature-dependent sex determination

• Based on variable enzyme activity in gonads

PLoS One 2013;8:e63599

Epigenetics

• DNA = identical• Gene = active vs. inactive

“readability”

• Epigenetic mechanisms:• DNA methylation• Histone modification• RNA silencing

Epigenetics

Epigenetics

• DNA = identical• Gene = active vs. inactive

“readability”

• Epigenetic mechanisms:• DNA methylation• Histone modification• RNA silencing• non coding RNA (ncRNA)• micro RNA (miRNA)

Epigenetics – an example

• Temperature-dependent sex determination

• Based on variable enzyme activity in gonads

• Based on different DNA methylation levels

PLoS One 2013;8:e63599

Heritable: Transgenerational effect?

Transgenerational effect

Biol Psychiatr 2010;68:408-15

Nat Rev Nephrol doi:10.1038/nrneph.2015.140

Causes of CAKUT

Epigenetics in CAKUT-

Some examples

Unilateral renal agenesis in 1 of twins

• Copy number variations: no

• SNPs: no

AJKD 2014;64:119-22

Unilateral renal agenesis in 1 of twins

• Copy number variations: no

• SNPs: no

• DNA methylation: 514 different regions

potential explanation?

AJKD 2014;64:119-22

Hypoplasia = low nephron number

• Uteroplacental insufficiency• Steroid exposure• Malnutrition• Protein restriction• Alcohol• Smoking• …

Kidney Int 2003;63:2118

Hypoplasia = low nephron number

• Uteroplacental insufficiency• Steroid exposure• Malnutrition• Protein restriction• Alcohol• Smoking• …

Kidney Int 2003;63:2118

~250,000 glom/kg

Cause of low nephron number

methylation of p53 promotor

Bax expression

apoptosis

nephron number

AJP Reg Integr Comp 2003;285:R962-70

Transgenerational effect - IUGR

Reprod Fertil Dev 2014;26:1032-43

Transgenerational effect - IUGR

Reprod Fertil Dev 2014;26:1032-43

Syst

olic

blo

od

pre

ssu

re(m

mH

g)

Epigenetic changes in IUGR

PLoS One 2010;5:e8887

Epigenetics in IUGR baboon kidney

J Med Primatol 2009;38:219-27

Transgenerational effect - Dutch famine

BJOG 2013;120:548-53

• Adult offspring (F2) of prenatally exposed F1 fathershigher weights and BMIs

• Adult offspring (F2) of prenatally exposed F1 mothersno effect

Epigenetics in CAKUT

• Limited data

• May lead to new insight in pathways

• May explain laterality

• May provide options towards modification

Conclusion: causes of CAKUT

Kidney Int 2011;79:23-32

Role of epigenetics in the development of CAKUT

Michiel SchreuderPediatric Nephrologist4 September 2015