Endothelin-1 production via placental (pro)renin receptor in a mouse model of preeclampsia

Mishima, Shiro; Mitsui, Takashi; Tani, Kazuhide; Ooba, Hikaru; Mitoma, Tomohiro; Ohira, Akiko; Maki, Jota; Kirino, Satoe; Eto, Eriko; Hayata, Keiji; Masuyama, Hisashi

doi:10.1016/j.placenta.2023.05.002

Cited by 4 publications

(5 citation statements)

References 35 publications

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“…The question therefore arises as to why there is variation in ATP6AP2 expression between the mouse placental junctional and labyrinth zones. Importantly, recent studies have similarly demonstrated that ATP6AP2 is abundant in the labyrinth zone of the mouse placenta ( Mishima et al, 2023 ). Immunohistochemical assessment of (P)RR localisation suggests that (P)RR is associated with S-TGCs within the placental labyrinth zone ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 97%

Placental deficiency of the (pro)renin receptor ((P)RR) reduces placental development and functional capacity

Schofield,

Kahl,

Rodrigues

et al. 2023

Front. Cell Dev. Biol.

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The (pro)renin receptor ((P)RR; also known as ATP6AP2) is a multifunctional receptor. The (P)RR activates the tissue renin-angiotensin system (RAS) and is also involved in regulating integral intracellular pathways such as V-ATPase and Wnt/β-catenin signalling. Given this, the (P)RR may be associated with essential pathways in placentation, however its role within the context of pregnancy remains poorly characterised. The first trimester/extravillous trophoblast cell line, HTR-8/SVneo, underwent an siRNA knockdown where they were incubated for 24 h with a negative control siRNA or siRNA targeting ATP6AP2 mRNA. xCELLigence real-time cell analysis was performed to assess the effect of ATP6AP2 mRNA knockdown on HTR-8/SVneo cell proliferation, migration, and invasion. In subsequent experiments, GFP-encoding lentiviral packaged gene-constructs were used to knockdown (P)RR expression in the trophectoderm of C57/BL6/CBA-F1 mouse blastocysts. Blastocysts were incubated for 6 h with vehicle (no-virus), control virus (non-targeting shRNA and GFP), or (P)RR-knockdown virus ((P)RR shRNA and GFP) before transfer into recipient pseudo-pregnant Swiss CD1 female mice. Fetal and placental tissues were collected and assessed at embryonic age (EA) 10 and 18. (P)RR levels were measured in the labyrinth zone of day 18 placentae and stereological Merz grid analysis was performed to determine the volumetric distribution of trophoblasts, fetal capillaries, and the maternal blood space. We showed that a reduction of ATP6AP2 expression in HTR-8/SVneo cells in vitro, impaired trophoblast proliferation, migration, and invasion. In vivo, decreasing placental labyrinth (P)RR expression adversely effected placental physiology, decreasing placental trophoblast number and total surface area available for exchange, while also increasing maternal blood space. Additionally, decreased (P)RR affected placental efficacy evident by the reduced fetal-placental weight ratio. Our study shows that the (P)RR is necessary for appropriate placental development and function.

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Section: Discussionmentioning

confidence: 97%

Placental deficiency of the (pro)renin receptor ((P)RR) reduces placental development and functional capacity

Schofield,

Kahl,

Rodrigues

et al. 2023

Front. Cell Dev. Biol.

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“…1 ) resulted in increased levels of endothelial dysfunction markers; VCAM-1, ICAM-1, and ET-1, suggesting that elevated s(P)RR has the potential to cause systemic maternal endothelial dysfunction. Recently, Mishima et al highlighted a connection between increased placental (P)RR and elevated plasma ET-1 secretion in a RUPP mouse model of preeclampsia [ 31 ]. Collectively, these data suggest a positive correlation with elevated (P)RR/s(P)RR and endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…A very recent study has also shown that targeting the s(P)RR may be a novel therapeutic pathway for the treatment of preeclampsia. Mice treated with the handle region peptide (HRP), another (P)RR inhibitor, reduced maternal blood pressure and proteinuria, inhibited endothelin-1 production and improved fetal weights in a mouse model of preeclampsia (RUPP) [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

The soluble (pro)renin receptor promotes a preeclampsia-like phenotype both in vitro and in vivo

Schofield,

Delforce,

Pryor

et al. 2024

Hypertens Res

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Preeclampsia is classified as new-onset hypertension coupled with gross endothelial dysfunction. Placental (pro)renin receptor ((P)RR) and plasma soluble (P)RR (s(P)RR) are elevated in patients with preeclampsia. Thus, we aimed to interrogate the role (P)RR may play in the pathogenesis of preeclampsia. Human uterine microvascular endothelial cells (HUtMECs, n = 4) were cultured with either; vehicle (PBS), 25–100 nM recombinant s(P)RR, or 10 ng/ml TNF-a (positive control) for 24 h. Conditioned media and cells were assessed for endothelial dysfunction markers via qPCR, ELISA, and immunoblot. Angiogenic capacity was assessed through tube formation and adhesion assays. Additionally, pregnant rats were injected with an adenovirus overexpressing s(P)RR from mid-pregnancy (day 8.5), until term (n = 6–7 dams/treatment). Maternal and fetal tissues were assessed. HUtMECs treated with recombinant s(P)RR displayed increased expression of endothelial dysfunction makers including vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and endothelin-1 mRNA expression (P = 0.003, P = 0.001, P = 0.009, respectively), along with elevated endothelin-1 protein secretion (P < 0.001) compared with controls. Recombinant s(P)RR impaired angiogenic capacity decreasing the number of branches, total branch length, and mesh area (P < 0.001, P = 0.004, and P = 0.009, respectively), while also increasing vascular adhesion (P = 0.032). +ADV rats exhibited increased systolic (P = 0.001), diastolic (P = 0.010), and mean arterial pressures (P = 0.012), compared with -ADV pregnancies. Renal arteries from +ADV-treated rats had decreased sensitivity to acetylcholine-induced relaxation (P = 0.030), compared with -ADV pregnancies. Our data show that treatment with s(P)RR caused hypertension and growth restriction in vivo and caused marked endothelial dysfunction in vitro. These findings demonstrate the significant adverse actions of s(P)RR on vascular dysfunction that is characteristic of the preeclamptic phenotype.

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“…39 REN is a renal peptide hormone that plays a role in regulating blood pressure and fluid balance. 26 TOX3 is a transcription factor that plays a role in regulating gene expression and cell proliferation. 40 Yang et al investigated the expression and role of TOX high mobility group box family member 3 in CRC.…”

Section: Discussionmentioning

confidence: 99%

“…The mRNA expression levels were normalized to GAPDH mRNA level and calculated using the 2 ÀΔΔCt method. The primer sequences were available in the previous references, including CD24, 21 FHL2, 22 GPM6A, 23 HOXD8, 24 NAP1L5, 25 REN, 26 and TOX3. 27…”

Section: Reverse Transcription-quantitative Polymerase Chain Reactionmentioning

confidence: 99%

Integrative analysis from multi‐center studies identifies a weighted gene co‐expression network analysis‐based Tregs signature in ovarian cancer

Cao,

Liu,

et al. 2023

Environmental Toxicology

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Ovarian cancer (OC) is a malignancy associated with poor prognosis and has been linked to regulatory T cells (Tregs) in the immune microenvironment. Nevertheless, the association between Tregs‐related genes (TRGs) and OC prognosis remains incompletely understood. The xCell algorithm was used to analyze Tregs scores across multiple cohorts. Weighted gene co‐expression network analysis (WGCNA) was utilized to identify potential TRGs and molecular subtypes. Furthermore, we used nine machine learning algorithms to create risk models with prognostic indicators for patients. Reverse transcription‐quantitative polymerase chain reaction and immunofluorescence staining were used to demonstrate the immunosuppressive ability of Tregs and the expression of key TRGs in clinical samples. Our study found that higher Tregs scores were significantly correlated with poorer overall survival. Recurrent patients exhibited increased Tregs infiltration and reduced CD8+ T cell. Moreover, molecular subtyping using seven key TRGs revealed that subtype B exhibited higher enrichment of multiple oncogenic pathways and had a worse prognosis. Notably, subtype B exhibited high Tregs levels, suggesting immune suppression. In addition, we validated machine learning‐derived prognostic models across multiple platform cohorts to better distinguish patient survival and predict immunotherapy efficacy. Finally, the differential expression of key TRGs was validated using clinical samples. Our study provides novel insights into the role of Tregs in the immune microenvironment of OC. We identified potential therapeutic targets derived from Tregs (CD24, FHL2, GPM6A, HOXD8, NAP1L5, REN, and TOX3) for personalized treatment and created a machining learning‐based prognostic model for OC patients, which could be useful in clinical practice.

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Endothelin-1 production via placental (pro)renin receptor in a mouse model of preeclampsia

Cited by 4 publications

References 35 publications

Placental deficiency of the (pro)renin receptor ((P)RR) reduces placental development and functional capacity

Placental deficiency of the (pro)renin receptor ((P)RR) reduces placental development and functional capacity

The soluble (pro)renin receptor promotes a preeclampsia-like phenotype both in vitro and in vivo

Integrative analysis from multi‐center studies identifies a weighted gene co‐expression network analysis‐based Tregs signature in ovarian cancer

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