Candesartan Does Not Activate PPARγ and Its Target Genes in Early Gestation Trophoblasts

Neuper, Lena; Kummer, Daniel; Forstner, Désirée; Guettler, Jacqueline; Ghaffari-Tabrizi-Wizsy, Nassim; Fischer, Cornelius; Juch, Herbert; Nonn, Olivia; Gauster, Martin

doi:10.3390/ijms232012326

Open AccessArticle

Candesartan Does Not Activate PPARγ and Its Target Genes in Early Gestation Trophoblasts

by

Lena Neuper

¹,

Daniel Kummer

¹,

Désirée Forstner

¹

,

Jacqueline Guettler

¹

,

Nassim Ghaffari-Tabrizi-Wizsy

²,

Cornelius Fischer

³,

Herbert Juch

^1,4,

Olivia Nonn

^1,5,6,7,*

and

Martin Gauster

¹

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria

²

Division of Immunology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, 8010 Graz, Austria

³

Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany

⁴

Diagnostic and Research Institute for Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, 8010 Graz, Austria

⁵

Experimental and Clinical Research Center, a Cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité—Universitätsmedizin Berlin, 13125 Berlin, Germany

⁶

Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, 10117 Berlin, Germany

⁷

Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2022, 23(20), 12326; https://doi.org/10.3390/ijms232012326

Submission received: 31 August 2022 / Revised: 8 October 2022 / Accepted: 10 October 2022 / Published: 14 October 2022

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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Abstract

Angiotensin II receptor 1 blockers are commonly used to treat hypertension in women of childbearing age. While the fetotoxic effects of these drugs in the second and third trimesters of pregnancy are well documented, their possible impacts on placenta development in early gestation are unknown. Candesartan, a member of this group, also acts as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, a key regulator shown to be important for placental development. We have previously shown that trophoblasts do not express the candesartan target–receptor angiotensin II type 1 receptor AGTR1. This study investigated the possible role of candesartan on trophoblastic PPARγ and its hallmark target genes in early gestation. Candesartan did not affect the PPARγ protein expression or nuclear translocation of PPARγ. To mimic extravillous trophoblasts (EVTs) and cytotrophoblast/syncytiotrophoblast (CTB/SCT) responses to candesartan, we used trophoblast cell models BeWo (for CTB/SCT) and SGHPL-4 (EVT) cells as well as placental explants. In vitro, the RT-qPCR analysis showed no effect of candesartan treatment on PPARγ target genes in BeWo or SGHPL-4 cells. Treatment with positive control rosiglitazone, another PPARγ agonist, led to decreased expressions of LEP and PPARG1 in BeWo cells and an increased expression of PPARG1 in SGHPL-4 cells. Our previous data showed early gestation–placental AGTR1 expression in fetal myofibroblasts only. In a CAM assay, AGTR1 was stimulated with angiotensin II and showed increased on-plant vessel outgrowth. These results suggest candesartan does not negatively affect PPARγ or its target genes in human trophoblasts. More likely, candesartan from maternal serum may first act on fetal-placental AGTR1 and influence angiogenesis in the placenta, warranting further research.

Keywords: candesartan; PPARγ; placenta; trophoblast; first-trimester pregnancy; rosiglitazone; teratogenic; angiotensin II

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MDPI and ACS Style

Neuper, L.; Kummer, D.; Forstner, D.; Guettler, J.; Ghaffari-Tabrizi-Wizsy, N.; Fischer, C.; Juch, H.; Nonn, O.; Gauster, M. Candesartan Does Not Activate PPARγ and Its Target Genes in Early Gestation Trophoblasts. Int. J. Mol. Sci. 2022, 23, 12326. https://doi.org/10.3390/ijms232012326

AMA Style

Neuper L, Kummer D, Forstner D, Guettler J, Ghaffari-Tabrizi-Wizsy N, Fischer C, Juch H, Nonn O, Gauster M. Candesartan Does Not Activate PPARγ and Its Target Genes in Early Gestation Trophoblasts. International Journal of Molecular Sciences. 2022; 23(20):12326. https://doi.org/10.3390/ijms232012326

Chicago/Turabian Style

Neuper, Lena, Daniel Kummer, Désirée Forstner, Jacqueline Guettler, Nassim Ghaffari-Tabrizi-Wizsy, Cornelius Fischer, Herbert Juch, Olivia Nonn, and Martin Gauster. 2022. "Candesartan Does Not Activate PPARγ and Its Target Genes in Early Gestation Trophoblasts" International Journal of Molecular Sciences 23, no. 20: 12326. https://doi.org/10.3390/ijms232012326

APA Style

Neuper, L., Kummer, D., Forstner, D., Guettler, J., Ghaffari-Tabrizi-Wizsy, N., Fischer, C., Juch, H., Nonn, O., & Gauster, M. (2022). Candesartan Does Not Activate PPARγ and Its Target Genes in Early Gestation Trophoblasts. International Journal of Molecular Sciences, 23(20), 12326. https://doi.org/10.3390/ijms232012326

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Candesartan Does Not Activate PPARγ and Its Target Genes in Early Gestation Trophoblasts

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