m.schreuder has documented that he has no relevant ... · pdf filencp nephrol 2008;4:312. ......
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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