B P LARKIN1, L T NGUYEN1, S J GLASTRAS1,2, M HOU3, H CHEN4, R WANG1, C A POLLOCK1, S SAAD1,4
1Renal Research Laboratory, Kolling Institute of Medical Research, 2Department of Diabetes, Endocrinology and Metabolism, Royal North Shore Hospital, 3Children’s Hospital of Soochow University, 4School of Life Sciences, University of Technology Sydney
Aim: To ascertain whether administering low-dose hydralazine during gestation in mouse models of maternal and diet-induced obesity interrupts fetal programming of chronic kidney disease (CKD) in offspring.
Background: Maternal obesity promotes CKD in offspring. Fetal DNA methylation has been implicated in the transgenerational programming of adult diseases. At low doses, hydralazine has been shown to induce DNA demethylation, suggesting a role in preventing maternal-obesity related CKD in offspring.
Methods: Female C57BL/6 mice received high fat diet (HFD) or chow prior to mating, during gestation and lactation. During gestation, dams received subcutaneous hydralazine (5 mg/kg) or saline thrice-weekly. Male offspring were weaned to HFD or chow and sacrificed at week 32. Biometric and metabolic parameters, renal global DNA methylation, renal functional and structural changes and markers of fibrosis, inflammation and oxidative stress were assessed. Whole epigenome analysis and gene expression were determined by reduced representation bisulfite sequencing and real-time PCR respectively.
Results: Gene methylation profiles were determined in the offspring kidneys. Renal global DNA methylation was increased by maternal obesity (p<0.05) and diet-induced obesity (p<0.01) in the offspring compared to control, both were attenuated by gestational hydralazine. Increased albuminuria (p<0.0001), glomerulosclerosis (p<0.0001) and serum creatinine (p<0.05) were seen in obese offspring of obese mothers and these were significantly improved by gestational administration of hydralazine. Renal fibrosis and oxidative stress were significantly increased in obese offspring of lean mothers (both p<0.01) and attenuated by gestational hydralazine.
Conclusion: Maternal obesity induced CKD in association with fetal epigenetic changes. Gestational hydralazine was renoprotective in offspring exposed to maternal obesity and/or dietary obesity, supporting its use in the prevention of CKD in offspring due to maternal obesity and postnatal HFD.
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.