scholarly journals Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248854
Author(s):  
Benjamin P. Larkin ◽  
Sonia Saad ◽  
Sarah J. Glastras ◽  
Long T. Nguyen ◽  
Miao Hou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Methylation ◽  
Fetal Programming ◽  
High Fat Diet ◽  
Renal Fibrosis ◽  
Low Dose ◽  
Maternal Obesity ◽  
Metabolic Parameters ◽  
Global Dna Methylation ◽  
High Fat

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.

scholarly journals Novel Role of Gestational Hydralazine in Limiting Maternal and Dietary Obesity-Related Chronic Kidney Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Benjamin P. Larkin ◽  
Long T. Nguyen ◽  
Miao Hou ◽  
Sarah J. Glastras ◽  
Hui Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Dna Methylation ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Low Dose ◽  
Maternal Obesity ◽  
Global Dna Methylation ◽  
Dietary Obesity ◽  
And Oxidative Stress

BackgroundMaternal obesity is a risk factor for chronic kidney disease (CKD) in offspring, underpinning the theory of the developmental origins of health and disease. DNA methylation has been implicated in the programming of adult chronic disease by maternal obesity, therefore, DNA demethylating agents may mitigate offspring risk of disease. In rodent models, low-dose hydralazine has previously been shown to reduce renal fibrosis via DNA demethylation. We used mouse models of maternal obesity and offspring obesity to determine whether administration of low-dose hydralazine during gestation can prevent fetal programming of CKD in offspring.MethodsFemale 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 weaned to HFD or chow, which continued until endpoint at 32 weeks. Biometric and metabolic parameters, renal global DNA methylation, renal functional and structural changes, and renal markers of fibrosis, inflammation and oxidative stress were assessed at endpoint.ResultsOffspring exposed to maternal obesity or diet-induced obesity had significantly increased renal global DNA methylation, together with other adverse renal effects including albuminuria, glomerulosclerosis, renal fibrosis, and oxidative stress. Offspring exposed to gestational hydralazine had significantly reduced renal global DNA methylation. In obese offspring of obese mothers, gestational hydralazine significantly decreased albuminuria, glomerulosclerosis, and serum creatinine. Obese offspring of hydralazine-treated lean mothers displayed reduced markers of renal fibrosis and oxidative stress.ConclusionGestational hydralazine decreased renal global DNA methylation and exerted renoprotective effects in offspring. This supports a potential therapeutic effect of hydralazine in preventing maternal obesity or dietary obesity-related CKD, through an epigenetic mechanism.

scholarly journals High-fat diet-induced and genetically inherited obesity differentially alters DNA methylation profile in the germline of adult male rats

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Sharvari S. Deshpande ◽  
Harishankar Nemani ◽  
Gandhimathi Arumugam ◽  
Avinash Ravichandran ◽  
Nafisa H. Balasinor
Keyword(s):  
Dna Methylation ◽  
Real Time ◽  
Real Time Pcr ◽  
High Fat Diet ◽  
Male Rats ◽  
Global Dna Methylation ◽  
High Fat ◽  
Differential Effects ◽  
Male Germline ◽  
Embryo Loss

Abstract Background Paternal obesity has been associated with reduced live birth rates. It could lead to inheritance of metabolic disturbances to the offspring through epigenetic mechanisms. However, obesity is a multifactorial disorder with genetic or environmental causes. Earlier we had demonstrated differential effects of high-fat diet-induced obesity (DIO) and genetically inherited obesity (GIO) on metabolic, hormonal profile, male fertility, and spermatogenesis using two rat models. The present study aimed to understand the effect of DIO and GIO on DNA methylation in male germline, and its subsequent effects on the resorbed (post-implantation embryo loss) and normal embryos. First, we assessed the DNA methylation enzymatic machinery in the testis by Real-Time PCR, followed global DNA methylation levels in spermatozoa and testicular cells by ELISA and flow cytometry, respectively. Further, we performed Methylation Sequencing in spermatozoa for both the groups. Sequencing data in spermatozoa from both the groups were validated using Pyrosequencing. Expression of the differentially methylated genes was assessed in the resorbed and normal embryos sired by the DIO group using Real-Time PCR for functional validation. Results We noted a significant decrease in Dnmt transcript and global DNA methylation levels in the DIO group and an increase in the GIO group. Sequencing analysis showed 16,966 and 9113 differentially methylated regions in the spermatozoa of the DIO and GIO groups, respectively. Upon pathway analysis, we observed genes enriched in pathways involved in embryo growth and development namely Wnt, Hedgehog, TGF-beta, and Notch in spermatozoa for both the groups, the methylation status of which partially correlated with the gene expression pattern in resorbed and normal embryos sired by the DIO group. Conclusion Our study reports the mechanism by which diet-induced and genetically inherited obesity causes differential effects on the DNA methylation in the male germline that could be due to a difference in the white adipose tissue accumulation. These differences could either lead to embryo loss or transmit obesity-related traits to the offspring in adult life.

scholarly journals Assessment of DNA Methylation and Oxidative Changes in the Heart and Brain of Rats Receiving a High-Fat Diet Supplemented with Various Forms of Chromium

Animals ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1470
Author(s):  
Wojciech Dworzański ◽  
Ewelina Cholewińska ◽  
Bartosz Fotschki ◽  
Jerzy Juśkiewicz ◽  
Piotr Listos ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Fat Diet ◽  
Protein Carbonyl ◽  
Global Dna Methylation ◽  
Standard Diet ◽  
Epigenetic Changes ◽  
Oxidation Reactions ◽  
High Fat ◽  
Repair Enzymes ◽  
The Brain

The aim of the study was to determine how feeding rats a high-fat diet supplemented with various forms of chromium affects DNA methylation and oxidation reactions as well as the histology of heart and brain tissue. The rats received standard diet or high-fat diet and chromium at 0.3 mg/kg body weight (BW) in form of chromium (III) picolinate, chromium (III)-methionine, or nano-sized chromium. The content of malondialdehyde (MDA), protein carbonyl (PC), and 8-hydroxydeoxyguanosine (8-OHDG), the level of global DNA methylation and the activity of selected DNA repair enzymes were determined in the blood. In the brain and heart, the content of MDA, PC, 8-OHDG, and levels of global DNA methylation were determined. The brain was subjected to histological examination. The use of a high-fat diet was found to intensify epigenetic changes and oxidation reactions in the heart and brain. It was concluded that epigenetic changes and oxidation of lipids, proteins, and DNA in the heart and brain of rats resulting from the use of a high-fat diet cannot be limited by supplementing the diet with chromium. It was established that the use of chromium to supplement a high-fat diet intensifies the negative epigenetic and oxidative changes in the heart and brain, especially in the case of chromium nanoparticles.

scholarly journals Oridonin Attenuates Diabetes‑Induced Renal Fibrosis via Inhibition of the TXNIP/NLRP3 and NF‑κB Pathway in Rats

2021 ◽  
Author(s):  
Gengzhen Huang ◽  
Yaodan Zhang ◽  
Yingying Zhang ◽  
Xiaotao Zhou ◽  
Yuan Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Function ◽  
High Fat Diet ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Treated Group ◽  
Diabetic Rats ◽  
Inflammatory Factors ◽  
High Fat ◽  
Rabdosia Rubescens

Abstract Background: Oxidative stress and its induced inflammation are important pathological processes of diabetic nephropathy (DN). Oridonin, a component isolated from Rabdosia rubescens, possesses remarkable anti-inflammatory, immunoregulatory properties, it is also a newly reported NLRP3 inhibitor. However, the renoprotective effects of Oridonin and the underlying molecular mechanisms have not been explored in DN. We hypothesized that Oridonin could reduce NLRP3 pathway and ameliorate diabetes‑induced renal fibrosis.Methods: We used STZ-induced diabetic rats combined high-fat diet to establish a T2DM animal model, and then treated with Oridonin (10, 20 mg/kg/day) for two weeks. Kidney function and renal fibrosis were assessed. In addition, the expression of inflammatory factors and fibrotic markers were analyzed by western blot.Results: Oridonin treatment preserved kidney function and markedly limited the renal fibrosis size in diabetic rats. The renal fibrotic markers were inhibited in the 10 mg/kg/day group and 20 mg/kg/day group compared to the T2DM group. Moreover, the expression levels of TXNIP/NLRP3 and NF‑κB pathway were decreased in the Oridonin treatment group compared to non-treated group. Conclusions: The NLRP3-inflammasome inhibitor Oridonin reduces renal fibrosis and preserves kidney function in T2DM rat model, which indicates potential therapeutic effect of Oridonin on DN.

scholarly journals The short-term high fat diet-induced increase in %5-methylcytosine expression in peripheral blood T lymphocytes, is attenuated by low-dose aspirin

2019 ◽  
Author(s):  
Tinashe Mutize ◽  
Phiwayinkosi V. Dludla ◽  
Zibusiso Mkandla ◽  
Bongani B. Nkambule
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
High Fat Diet ◽  
Low Dose ◽  
High Fat ◽  
Short Term ◽  
Dose Aspirin ◽  
Low Dose Aspirin

AbstractObjectiveTo assess peripheral lymphocyte DNA methylation profiles in prediabetes using a high fat-diet-fed C57BL/6 animal model. We further evaluated whether low dose-aspirin, or low-dose aspirin in combination with metformin, could modulate global DNA methylation levels in peripheral blood lymphocytes.MethodsTwenty-eight (28) male C57BL/6 mice were used in two experimental phases. The first experiment involved animals (n=16) which were randomised to receive a low-fat diet (LFD) or high-fat diet (HFD) (n = 8/group) for 10 weeks. Whereas in the second experiment, HFD-fed mice (n=15) were randomised into 3 treatment groups, a low-dose aspirin (LDA), LDA and metformin group, and a clopidogrel group. DNA methylation profiles of were determined using flow cytometry.ResultsThe HFD group showed moderate weight gain and elevated postprandial blood glucose levels when compared to the LFD group after 2 weeks of HFD-feeding (p < 0.05). Interestingly, the HFD group had elevated levels of T cells expressing high levels %5-methylcytosine (p<0, 05). Notably, these elevated levels were lowered by short-term low-dose aspirin treatment.DiscussionT cells are involved in the propagation of the inflammatory response. Persistent T cell activation promotes chronic inflammation and insulin resistance. Low-dose aspirin may be effective in modulating T cell-specific global methylation.

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