Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet.
<h4>Background</h4>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 h...
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Public Library of Science (PLoS)
2021-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0248854&type=printable |
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| author | Benjamin P Larkin Sonia Saad Sarah J Glastras Long T Nguyen Miao Hou Hui Chen Rosy Wang Carol A Pollock |
| author_facet | Benjamin P Larkin Sonia Saad Sarah J Glastras Long T Nguyen Miao Hou Hui Chen Rosy Wang Carol A Pollock |
| author_sort | Benjamin P Larkin |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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. |
| format | Article |
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| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-ebda3bcbabc04108832078650bdb80972025-08-20T02:54:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01163e024885410.1371/journal.pone.0248854Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet.Benjamin P LarkinSonia SaadSarah J GlastrasLong T NguyenMiao HouHui ChenRosy WangCarol A Pollock<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0248854&type=printable |
| spellingShingle | Benjamin P Larkin Sonia Saad Sarah J Glastras Long T Nguyen Miao Hou Hui Chen Rosy Wang Carol A Pollock Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet. PLoS ONE |
| title | Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet. |
| title_full | Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet. |
| title_fullStr | Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet. |
| title_full_unstemmed | Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet. |
| title_short | Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet. |
| title_sort | low dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0248854&type=printable |
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