B LARKIN1, L NGUYEN1, S GLASTRAS1,2, H CHEN3, C POLLOCK1, S SAAD1,3
1Renal Research Laboratory, Kolling Institute Of Medical Research, St Leonards, Australia, 2Department of Diabetes, Endocrinology and Metabolism, Royal North Shore Hospital, St Leonards, Australia, 3School of Life Sciences, University of Technology Sydney, Sydney, Australia
Aim: To identify differentially methylated genes in offspring of obese versus lean mothers using a mouse model of maternal obesity.
Background: Adverse conditions during fetal development predispose offspring to adult diseases, supporting the theory of fetal programming. DNA methylation is suggested as a mechanism by which maternal obesity induces fetal programming. As maternal obesity predisposes offspring to chronic kidney disease (CKD), we hypothesised that DNA methylation differences may explain how maternal obesity programs offspring CKD.
Methods: Maternal obesity was modelled by feeding female C57BL/6 mice a high fat diet before breeding, during gestation and lactation. Control dams received chow. Male offspring were weaned to chow on postnatal day 20, and were sacrificed at 32 weeks of age. DNA was extracted from kidneys and blood of offspring. Reduced representation bisulfite sequencing identified genes which were differentially methylated due to maternal obesity. Real-time PCR was used to assess gene expression. A post-hoc analysis of differentially methylated genes identified those with relevance to CKD and metabolic conditions.
Results: In adult offspring of obese versus lean mothers, 11 genes were significantly differentially methylated in the kidney. Of these, 5 genes also showed significant differential methylation in the blood. An additional 10 genes were differentially methylated in the blood only. Renal mRNA expression of 4 genes (Rcsd1, Cdk8, Taco1 and Axin2) were significantly regulated, confirming functional changes in the offspring due to epigenetic regulation.
Conclusion: Maternal obesity induced differential gene methylation in the kidneys and blood of adult offspring. Several of these genes have shown high relevance to kidney fibrosis, diabetes or obesity, and their epigenetic regulation may explain the fetal programming of CKD by maternal obesity.
Benjamin Larkin is a nephrologist and has recently completed his PhD, for which he received a Jacquot Research Entry Scholarship. His research interests include the roles of obesity, maternal obesity and epigenetics in chronic kidney disease, and the use of DNA demethylating agents to prevent CKD progression.