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Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats

Pregnancy induces maternal renal adaptations that include increased glomerular filtration rate and renal blood flow which can be compromised in obstetrical complications such as preeclampsia. Brown Norway (BN) rat pregnancies are characterized by placental insufficiency, maternal hypertension, and p...

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Autores principales: Chen, Zhong, Wang, Charles, Blood, Arlin, Bragg, Shannon, Mata-Greenwood, Eugenia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202892/
https://www.ncbi.nlm.nih.gov/pubmed/35709218
http://dx.doi.org/10.1371/journal.pone.0269792
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author Chen, Zhong
Wang, Charles
Blood, Arlin
Bragg, Shannon
Mata-Greenwood, Eugenia
author_facet Chen, Zhong
Wang, Charles
Blood, Arlin
Bragg, Shannon
Mata-Greenwood, Eugenia
author_sort Chen, Zhong
collection PubMed
description Pregnancy induces maternal renal adaptations that include increased glomerular filtration rate and renal blood flow which can be compromised in obstetrical complications such as preeclampsia. Brown Norway (BN) rat pregnancies are characterized by placental insufficiency, maternal hypertension, and proteinuria. We hypothesized that BN pregnancies would show renal functional, anatomical, or molecular features of preeclampsia. We used the Sprague-Dawley (CD) rat as a model of normal pregnancy. Pregnancy increased the glomerular filtration rate by 50% in CD rats and 12.2% in BN rats compared to non-pregnancy, and induced proteinuria only in BN rats. BN pregnancies showed a decrease in maternal plasma calcitriol levels, which correlated with renal downregulation of 1-alpha hydroxylase and upregulation of 24-hydroxylase. RNA sequencing revealed that pregnancy induced 297 differentially expressed genes (DEGs) in CD rats and 174 DEGs in BN rats, indicating a 70% increased response to pregnancy in CD compared to BN rats. Pregnancy induced activation of innate immune pathways such as ‘Role of Pattern Recognition Receptors’, and ‘Interferon signaling’ with interferon regulatory factor 7 as a common upregulated upstream factor in both rat strains. Comparison of rat strain transcriptomic profiles revealed 475 DEGs at non-pregnancy and 569 DEGs at pregnancy with 205 DEGs shared at non-pregnancy (36%), indicating that pregnancy interacted with rat strain in regulating 64% of the DEGs. Pathway analysis revealed that pregnancy induced a switch in renal transcriptomics in BN rats from ‘inhibition of renal damage’ to ‘acute phase reaction’, ‘recruitment of immune cells’ and ‘inhibition of 1,25-(OH)(2)-vitamin D synthesis’. Key upstream regulators included peroxisome-proliferator-activated receptor alpha (PPARA), platelet-derived growth factor B dimer (PDGF-BB), and NF-kB p65 (RELA). DNA methylome profiling by reduced representation bisulfite sequencing studies revealed that the DEGs did not correlate with changes in promoter methylation. In sum, BN rat kidneys respond to pregnancy-specific signals with an increase in pro-inflammatory gene networks and alteration of metabolic pathways including vitamin D deficiency in association with mild proteinuria and blunted GFR increase. However, the lack of glomerular endotheliosis and mild hypertension/proteinuria in pregnant BN rats limits the relevance of this rat strain for preeclampsia research.
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spelling pubmed-92028922022-06-17 Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats Chen, Zhong Wang, Charles Blood, Arlin Bragg, Shannon Mata-Greenwood, Eugenia PLoS One Research Article Pregnancy induces maternal renal adaptations that include increased glomerular filtration rate and renal blood flow which can be compromised in obstetrical complications such as preeclampsia. Brown Norway (BN) rat pregnancies are characterized by placental insufficiency, maternal hypertension, and proteinuria. We hypothesized that BN pregnancies would show renal functional, anatomical, or molecular features of preeclampsia. We used the Sprague-Dawley (CD) rat as a model of normal pregnancy. Pregnancy increased the glomerular filtration rate by 50% in CD rats and 12.2% in BN rats compared to non-pregnancy, and induced proteinuria only in BN rats. BN pregnancies showed a decrease in maternal plasma calcitriol levels, which correlated with renal downregulation of 1-alpha hydroxylase and upregulation of 24-hydroxylase. RNA sequencing revealed that pregnancy induced 297 differentially expressed genes (DEGs) in CD rats and 174 DEGs in BN rats, indicating a 70% increased response to pregnancy in CD compared to BN rats. Pregnancy induced activation of innate immune pathways such as ‘Role of Pattern Recognition Receptors’, and ‘Interferon signaling’ with interferon regulatory factor 7 as a common upregulated upstream factor in both rat strains. Comparison of rat strain transcriptomic profiles revealed 475 DEGs at non-pregnancy and 569 DEGs at pregnancy with 205 DEGs shared at non-pregnancy (36%), indicating that pregnancy interacted with rat strain in regulating 64% of the DEGs. Pathway analysis revealed that pregnancy induced a switch in renal transcriptomics in BN rats from ‘inhibition of renal damage’ to ‘acute phase reaction’, ‘recruitment of immune cells’ and ‘inhibition of 1,25-(OH)(2)-vitamin D synthesis’. Key upstream regulators included peroxisome-proliferator-activated receptor alpha (PPARA), platelet-derived growth factor B dimer (PDGF-BB), and NF-kB p65 (RELA). DNA methylome profiling by reduced representation bisulfite sequencing studies revealed that the DEGs did not correlate with changes in promoter methylation. In sum, BN rat kidneys respond to pregnancy-specific signals with an increase in pro-inflammatory gene networks and alteration of metabolic pathways including vitamin D deficiency in association with mild proteinuria and blunted GFR increase. However, the lack of glomerular endotheliosis and mild hypertension/proteinuria in pregnant BN rats limits the relevance of this rat strain for preeclampsia research. Public Library of Science 2022-06-16 /pmc/articles/PMC9202892/ /pubmed/35709218 http://dx.doi.org/10.1371/journal.pone.0269792 Text en © 2022 Chen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Chen, Zhong
Wang, Charles
Blood, Arlin
Bragg, Shannon
Mata-Greenwood, Eugenia
Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats
title Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats
title_full Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats
title_fullStr Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats
title_full_unstemmed Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats
title_short Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats
title_sort renal functional, transcriptome, and methylome adaptations in pregnant sprague dawley and brown norway rats
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202892/
https://www.ncbi.nlm.nih.gov/pubmed/35709218
http://dx.doi.org/10.1371/journal.pone.0269792
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