Benjamin P Larkin1, Sonia Saad1,2, Sarah J Glastras1,3, Long T Nguyen1, Miao Hou4, Hui Chen2, Rosy Wang1, Carol A Pollock1. 1. Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia. 2. School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia. 3. Department of Diabetes, Endocrinology and Metabolism, Royal North Shore Hospital, Sydney, Australia. 4. Department of Cardiology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.
Abstract
BACKGROUND: Maternal high fat diet (HFD) promotes chronic kidney disease (CKD) in offspring. This is in accordance with the theory of fetal programming, which suggests adverse conditions occurring in utero predispose offspring to chronic conditions later in life. DNA methylation has been proposed as a key mechanism by which fetal programming occurs and is implicated in CKD progression. DNA demethylating drugs may interrupt the fetal programming of CKD by maternal obesity. Hydralazine, an antihypertensive agent, demethylates DNA at low doses which do not reduce blood pressure. We used a mouse model of maternal obesity to determine whether gestational administration of low-dose hydralazine to mothers can prevent CKD in offspring. METHODS: C57BL/6 dams received HFD or chow from 6 weeks prior to mating and were administered subcutaneous hydralazine (5mg/kg) or saline thrice weekly during gestation. Male offspring were weaned to chow and were sacrificed at either postnatal week 9 or week 32. Biometric and metabolic parameters, renal global DNA methylation, renal structural and functional changes and markers of fibrosis, oxidative stress and inflammation were measured in offspring at weeks 9 and 32. RESULTS: In week 9 offspring, maternal HFD consumption did not significantly alter anthropometric or metabolic parameters, or renal global DNA methylation. Week 32 offspring had increased renal global DNA methylation, together with albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. Administration of low-dose hydralazine to obese mothers during gestation reduced renal global DNA methylation and renal fibrotic markers in week 32 offspring. CONCLUSION: Gestational hydralazine reduced renal global DNA methylation in offspring of obese mothers and attenuated maternal obesity-induced renal fibrosis. These data support the use of low-dose hydralazine as a demethylating agent to prevent CKD arising in offspring due to maternal HFD consumption.
BACKGROUND: Maternal high fat diet (HFD) promotes chronic kidney disease (CKD) in offspring. This is in accordance with the theory of fetal programming, which suggests adverse conditions occurring in utero predispose offspring to chronic conditions later in life. DNA methylation has been proposed as a key mechanism by which fetal programming occurs and is implicated in CKD progression. DNA demethylating drugs may interrupt the fetal programming of CKD by maternal obesity. Hydralazine, an antihypertensive agent, demethylates DNA at low doses which do not reduce blood pressure. We used a mouse model of maternal obesity to determine whether gestational administration of low-dose hydralazine to mothers can prevent CKD in offspring. METHODS: C57BL/6 dams received HFD or chow from 6 weeks prior to mating and were administered subcutaneous hydralazine (5mg/kg) or saline thrice weekly during gestation. Male offspring were weaned to chow and were sacrificed at either postnatal week 9 or week 32. Biometric and metabolic parameters, renal global DNA methylation, renal structural and functional changes and markers of fibrosis, oxidative stress and inflammation were measured in offspring at weeks 9 and 32. RESULTS: In week 9 offspring, maternal HFD consumption did not significantly alter anthropometric or metabolic parameters, or renal global DNA methylation. Week 32 offspring had increased renal global DNA methylation, together with albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. Administration of low-dose hydralazine to obese mothers during gestation reduced renal global DNA methylation and renal fibrotic markers in week 32 offspring. CONCLUSION: Gestational hydralazine reduced renal global DNA methylation in offspring of obese mothers and attenuated maternal obesity-induced renal fibrosis. These data support the use of low-dose hydralazine as a demethylating agent to prevent CKD arising in offspring due to maternal HFD consumption.
Authors: Björn Tampe; Ulrike Steinle; Désirée Tampe; Julienne L Carstens; Peter Korsten; Elisabeth M Zeisberg; Gerhard A Müller; Raghu Kalluri; Michael Zeisberg Journal: Kidney Int Date: 2016-09-28 Impact factor: 10.612
Authors: Sarah J Glastras; Hui Chen; Rachel Teh; Rachel T McGrath; Jason Chen; Carol A Pollock; Muh Geot Wong; Sonia Saad Journal: PLoS One Date: 2016-08-31 Impact factor: 3.240
Authors: Benjamin P Larkin; Long T Nguyen; Miao Hou; Sarah J Glastras; Hui Chen; Alen Faiz; Jason Chen; Rosy Wang; Carol A Pollock; Sonia Saad Journal: Diabetes Obes Metab Date: 2022-06-29 Impact factor: 6.408