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      Role for ovarian hormones in purinoceptor-dependent natriuresis

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          Abstract

          Background

          Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y 2 and P2Y 4 purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na + transport. Activation of these receptors inhibits epithelial Na + channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y 2 and P2Y 4 receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y 2 and P2Y 4) receptors regulating Na + excretion compared to male and OVX rats.

          Methods

          To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na + excretion in anesthetized male, ovary-intact female, and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y 2 and P2Y 4 receptors, and (iii) mRNA expression of their downstream effectors (PLC-1δ and ENaCα) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E 2, 0, 10, 100, and 1000 nM) to test whether E 2 increases mRNA expression of P2Y 2 and P2Y 4 receptors.

          Results

          Acute P2 inhibition attenuated urinary Na + excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y 2 and P2Y 4 mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y 2 receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E 2 dose-dependently upregulated P2Y 2 and P2Y 4 mRNA expression in mIMCD3.

          Conclusion

          These data suggest that ovary-intact females have enhanced P2Y 2 and P2Y 4-dependent regulation of Na + handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na + handling in premenopausal females.

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          Most cited references42

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          Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0

          Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting is vital to this process; it allows readers to assess the reliability of the findings and repeat or build upon the work of other researchers. The ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) were developed in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of ARRIVE on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This explanation and elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2.0, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature. This document also covers advice and best practice in the design and conduct of animal studies to support researchers in improving standards from the start of the experimental design process through to publication.
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            Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes.

            Estrogen receptors (ERs) act by regulating transcriptional processes. The classical mechanism of ER action involves estrogen binding to receptors in the nucleus, after which the receptors dimerize and bind to specific response elements known as estrogen response elements (EREs) located in the promoters of target genes. However, ERs can also regulate gene expression without directly binding to DNA. This occurs through protein-protein interactions with other DNA-binding transcription factors in the nucleus. In addition, membrane-associated ERs mediate nongenomic actions of estrogens, which can lead both to altered functions of proteins in the cytoplasm and to regulation of gene expression. The latter two mechanisms of ER action enable a broader range of genes to be regulated than the range that can be regulated by the classical mechanism of ER action alone. This review surveys our knowledge about the molecular mechanism by which ERs regulate the expression of genes that do not contain EREs, and it gives examples of the ways in which the genomic and nongenomic actions of ERs on target genes converge. Genomic and nongenomic actions of ERs that do not depend on EREs influence the physiology of many target tissues, and thus, increasing our understanding of the molecular mechanisms behind these actions is highly relevant for the development of novel drugs that target specific receptor actions.
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              Sexual Dimorphic Pattern of Renal Transporters and Electrolyte Homeostasis

              Compared with males, females have lower BP before age 60, blunted hypertensive response to angiotensin II, and a leftward shift in pressure natriuresis. This study tested the concept that this female advantage associates with a distinct sexual dimorphic pattern of transporters along the nephron. We applied quantitative immunoblotting to generate profiles of transporters, channels, claudins, and selected regulators in both sexes and assessed the physiologic consequences of the differences. In rats, females excreted a saline load more rapidly than males did. Compared with the proximal tubule of males, the proximal tubule of females had greater phosphorylation of Na + /H + exchanger isoform 3 (NHE3), distribution of NHE3 at the base of the microvilli, and less abundant expression of Na + /Pi cotransporter 2, claudin-2, and aquaporin 1. These changes associated with less bicarbonate reabsorption and higher lithium clearance in females. The distal nephrons of females had a higher abundance of total and phosphorylated Na + /Cl − cotransporter (NCC), claudin-7, and cleaved forms of epithelial Na + channel (ENaC) α and γ subunits, which associated with a lower baseline plasma K + concentration. A K + -rich meal increased the urinary K + concentration and decreased the level of renal phosphorylated NCC in females. Notably, we observed similar abundance profiles in female versus male C57BL/6 mice. These results define sexual dimorphic phenotypes along the nephron and suggest that lower proximal reabsorption in female rats expedites excretion of a saline load and enhances NCC and ENaC abundance and activation, which may facilitate K + secretion and set plasma K + at a lower level.
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                Author and article information

                Contributors
                emangohar@uabmc.edu
                Journal
                Biol Sex Differ
                Biol Sex Differ
                Biology of Sex Differences
                BioMed Central (London )
                2042-6410
                14 September 2020
                14 September 2020
                2020
                : 11
                : 52
                Affiliations
                GRID grid.265892.2, ISNI 0000000106344187, Division of Nephrology, Department of Medicine, , University of Alabama at Birmingham, ; 720 20th St S, Kaul 840, Birmingham, AL 35233 USA
                Author information
                http://orcid.org/0000-0003-0988-6445
                Article
                329
                10.1186/s13293-020-00329-0
                7490965
                32928299
                950b27bc-a226-487a-a124-8baeb57a16c9
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 27 March 2020
                : 1 September 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: K99DK119413
                Award ID: RO1 DK044628
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: K99HL144817
                Award ID: P01 HL 069999
                Award ID: P01 HL136267
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000968, American Heart Association;
                Award ID: 18CDA34110010
                Award ID: 15POST25090329
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Human biology
                purinoceptors,renal medulla,sodium excretion,ovariectomy
                Human biology
                purinoceptors, renal medulla, sodium excretion, ovariectomy

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