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. 2022 Mar 23;12(1):4953.
doi: 10.1038/s41598-022-08817-6.

Renalase and its receptor, PMCA4b, are expressed in the placenta throughout the human gestation

Melinda Wang #  1 , Tatiana Silva #  1 , Jessica M Toothaker  1   2 , Blake T McCourt  1   3 , Christine Shugrue  1   4 , Gary Desir  1   4   5 , Fred Gorelick  1   4   5   6 , Liza Konnikova  7   8   9   10   11
Affiliations

Renalase and its receptor, PMCA4b, are expressed in the placenta throughout the human gestation

Melinda Wang et al. Sci Rep. .

Abstract

Placental function requires organized growth, transmission of nutrients, and an anti-inflammatory milieu between the maternal and fetal interface, but placental factors important for its function remain unclear. Renalase is a pro-survival, anti-inflammatory flavoprotein found to be critical in other tissues. We examined the potential role of renalase in placental development. PCR, bulk RNA sequencing, immunohistochemistry, and immunofluorescence for renalase and its binding partners, PMCA4b and PZP, were performed on human placental tissue from second-trimester and full-term placentas separated into decidua, placental villi and chorionic plates. Quantification of immunohistochemistry was used to localize renalase across time course from 17 weeks to term. Endogenous production of renalase was examined in placental tissue and organoids. Renalase and its receptor PMCA4b transcripts and proteins were present in all layers of the placenta. Estimated RNLS protein levels did not change with gestation in the decidual samples. However, placental villi contained more renalase immunoreactive cells in fetal than full-term placental samples. RNLS co-labeled with markers for Hofbauer cells and trophoblasts within the placental villi. Endogenous production of RNLS, PMCA4b, and PZP by trophoblasts was validated in placental organoids. Renalase is endogenously expressed throughout placental tissue and specifically within Hofbauer cells and trophoblasts, suggesting a potential role for renalase in placental development and function. Future studies should assess renalase's role in normal and diseased human placenta.

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Conflict of interest statement

GD is a named inventor on several issued patents related to the discovery and therapeutic use of renalase. Renalase is licensed to Bessor Pharma, and GD holds an equity position in Bessor and its subsidiary Personal Therapeutics. There are no other competing interests for this manuscript.

Figures

Figure 1
Figure 1
RNLS is present in placental villi throughout gestation. (A) Cartoon image of a fetus with labeled parts of the placenta. Made with BioRender. (B) Expression of RNLS and its receptor, PMCA4b, in villi, chorionic plate (CP), and decidua in fetal and term tissue (n = 3 for both). TPM- transcripts per million reads. *p-value = 0.0250 (Term RNLS); p-value = 0.0107 (Term PMCA4b) upon post hoc analysis after nonparametric Kruskal Wallis (K-W) test. Alpha level = 0.05. (C) PCR analysis of term placental layers performed in duplicate n = 1. (D) RNLS labeling in placental villi throughout development during fetal and term-time points. (E) Representative placental villi labeling with black arrow pointing to a region of RNLS localization along the border of placental villi and * indicating cells staining for RNLS within the villi interstitium. Immunohistochemistry with hematoxylin staining for RNLS using m28-RNLS antibody at  20x (D) and  60x  (E). (E) Quantification of RNLS positive cells in placental villi during fetal and term-time points (n = 6). HPF-high-power field. *p-value < 0.0001 upon post hoc analysis after two-tailed Mann–Whitney test. All graphs use the mean for average values and standard error for error bars. Black arrow pointing at RNLS positive cells.
Figure 2
Figure 2
RNLS is detected in the decidua. (A) RNLS staining in decidua throughout development during fetal and term-time points. (B) Representative decidua with an arrow pointing to region of RNLS staining in a cell within the decidua. Immunohistochemistry with hematoxylin staining for RNLS using m28-RNLS antibody at  20x (A) and  60x (C). (C) Quantification of RNLS staining during fetal and term-time points in the decidua (n = 4). HPF-high-power field. Post hoc analysis completed after two-tailed Mann–Whitney test. All graphs use the mean for average values and standard error for error bars. Black arrow pointing at RNLS positive cells.
Figure 3
Figure 3
Fetal membranes contain RNLS. (A) RNLS labeling in amnion and chorion of the chorionic plate throughout development during fetal and term-time points. (B) Representative amnion and chorion RNLS staining with arrows pointing to regions of RNLS staining. Immunohistochemistry with hematoxylin staining for RNLS using m28-RNLS antibody at  20x (A) and 60x (B). Black arrow pointing at RNLS positive cells.
Figure 4
Figure 4
RNLS immunoreactivity is present in trophoblasts and macrophages within placental villi and decidua. (A) Immunofluorescence co-labeling with RNLS (red), vimentin (green, endothelium), DAPI (blue) of placental villi at  60x. (B) RNLS (red), SMA (green, smooth muscle actin, smooth muscle), and DAPI (blue) of placental villi at  60x. (C) RNLS (red), CD14 (green, Hofbauer cell), Cyt19 (white, cytokeratin 19, trophoblast), DAPI (blue) in placental villi at  60x. (D) RNLS (green), CD14 (red, Hofbauer cell) and DAPI (blue) of placental villi trophoblasts at  60x. (E) RNLS (green), Cyt19 (red, extravillous trophoblast, EVT), DAPI (blue) of placental decidua at  60x.
Figure 5
Figure 5
RNLS receptor and potential binding protein are present in placental villi; PMCA4b localizes to the same cells as RNLS. (A) RNLS (red), PMCA4b (green, RNLS receptor), and DAPI (blue) of placental villi at  60x; (B) RNLS (red), PZP (green, RNLS binding protein), DAPI (blue) of placental villi at  60x.
Figure 6
Figure 6
RNLS is produced endogenously in placental trophoblasts. (A) Hematoxylin and eosin stain of placental organoid at  40x; (B) immunohistochemistry staining of RNLS in placental organoid at  60x; (C) immunofluorescence of RNLS (red), Cyt19 (trophoblast, green), and DAPI (blue) of placental organoid at  60x.
Figure 7
Figure 7
Placental villi organoids express RNLS, its receptor PMCA4b, and the RNLS carrier protein, PZP. (A) Immunofluorescence co-staining with RNLS (red), PZP (green), DAPI (blue), and Cyt19 (white) of placental villi organoid at  20x and  60x. (B) Immunofluorescence co-staining with RNLS (red), PMCA4b (green), DAPI (blue), and Cyt19 (white) at  20x and  60x.
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References

    1. Turco MY, Moffett A. Development of the human placenta. Development. 2019;146:13. doi: 10.1242/dev.163428. - DOI - PubMed
    1. Xu J, et al. Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J. Clin. Investig. 2005;115:1275–1280. doi: 10.1172/JCI24066. - DOI - PMC - PubMed
    1. Wang Y, et al. Extracellular renalase protects cells and organs by outside-in signalling. J. Cell Mol. Med. 2017;21:1260–1265. doi: 10.1111/jcmm.13062. - DOI - PMC - PubMed
    1. Desir GV, Peixoto AJ. Renalase in hypertension and kidney disease. Nephrol. Dial. Transplant. 2014;29:22–28. doi: 10.1093/ndt/gft083. - DOI - PubMed
    1. Guo X, et al. Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer. Sci. Rep. 2016;6:1–10. doi: 10.1038/s41598-016-0001-8. - DOI - PMC - PubMed

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