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Fetal Renal DNA Methylation and Developmental Programming of Stress-Induced Hypertension in Growth-Restricted Male Mice

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Abstract

Fetal growth restriction (FGR) is associated with developmental programming of adult onset hypertension, which may be related to differences in nephron development. Prior studies showed that maternal nutrient restriction is associated with reduced nephrogenesis in rodents, especially in male progeny. We hypothesized that maternal genetic risk for FGR may similarly affect fetal kidney development, leading to adult onset hypertension. We employed an angiotensinogen (AGT) gene titration transgenic (TG) construct with 3 copies of the mouse AGT gene that mimics a common human genotype (AGT A[-6]G) associated with FGR. We investigated whether FGR in 2-copy (wild type, [WT]) progeny from 3-copy TG dams leads to developmental programming differences in kidney development and adult blood pressure compared with age- and sex-matched controls. Progeny were tested in the late fetal period (e17.5), neonatal period (2 weeks of age), and as young adults (12 weeks). We measured weights, tested for renal oxidative stress, compared renal DNA methylation profiles, counted the number of glomeruli, and measured adult blood pressure ± stress. Progeny from TG dams were growth restricted with evidence of renal oxidative stress, males showed fetal renal DNA hypermethylation, they had fewer glomeruli, and they developed stress-induced hypertension as adults. Their female siblings did not share this pathology and instead resembled progeny from WT dams. Surprisingly, glomerular counts in the neonatal period were not different between sexes or maternal genotypes. In turn, we suspect that differences in fetal renal DNA methylation may affect the long-term viability of glomeruli, rather than reducing nephrogenesis.

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Abbreviations

AGT:

Angiotensinogen

MAP:

Mean arterial pressure

RAS:

Renin-angiotensin system

TG:

Transgenic (3 copies of the murine AGT)

WT:

Wild type (2 copies of the murine AGT gene)

pTG:

2-Copy (WT) progeny from 3-copy (TG) dams

pWT:

2-Copy (WT) progeny from WT dams

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Acknowledgments

We thank John Yucel from Data Sciences International for his assistance with blood pressure and locomotor activity methods. We are also indebted to Drs. Douglas Weeks, Lori Woods, and Kent Thornburg for their years of mentorship and support.

Funding

This study was funded by the National Institute of Child Health and Human Development (1R21HD068896-01A1), the Office of Women’s Health Research: Oregon K12 BIRCWH (HD043488-08), Society of Reproductive Investigation, and the Oregon Medical Research Foundation. Centre for Stochastic Geometry and Advanced Bioimaging was supported by Villum Foundation.

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Authors and Affiliations

  1. Departments of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA

    Elizabeth DuPriest, Jessica Hebert, Mayu Morita, Nicole Marek, Emily E. K. Meserve, Nicole Andeen & Terry Morgan

  2. Division of Natural Science and Health, Warner Pacific University, Portland, OR, USA

    Elizabeth DuPriest

  3. Department of Biology, Portland State University, Portland, OR, USA

    Jessica Hebert

  4. Department of Anatomic & Clinical Pathology, Maine Medical Center, Portland, ME, USA

    Emily E. K. Meserve

  5. College of Public Health and Human Sciences, Oregon State University, Corvallis, OR, USA

    E. Andres Houseman

  6. Departments of Cardiovascular Medicine, Oregon Health & Science University, Portland, OR, USA

    Yue Qi

  7. Department of Zoology, King Saud University, Riyadh, Saudi Arabia

    Saleh Alwasel

  8. Core Centre for Molecular Morphology, Department of Clinical Medicine, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University, Aarhus, Denmark

    Jens Nyengaard

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  1. Elizabeth DuPriest
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DuPriest, E., Hebert, J., Morita, M. et al. Fetal Renal DNA Methylation and Developmental Programming of Stress-Induced Hypertension in Growth-Restricted Male Mice. Reprod. Sci. 27, 1110–1120 (2020). https://doi.org/10.1007/s43032-019-00121-5

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