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Estrogen dependent CD4+ T cell specific transcriptomic pathways identified in premenopausal protection against hypertension

ABSTRACT: Background: Premenopausal females are protected against T cell-dependent immune activation and development of angiotensin II (Ang II) hypertension compared to males and postmenopausal females. Therefore, the current study hypothesized that specific CD4+ T cell pathways are regulated by estrogen signlaing and Ang II, and contribute to sex differences in T cell cytokine secretion and renal inflammation. Methods and Results: Transcriptomic profiles of CD4+ T cells isolated from spleens of untreated (Control) and Ang II infused (Ang II) premenopausal C57BL/6 mice were examined via RNA sequencing. Ang II significantly regulated expression of 34 genes, of which 11 (Upregulated: CD163, PRG2, S100A9, MPO, CTSG, NGP, LCN2, S100A8; Downregulated: MARCO, IL1b, HSPA1B) were confirmed by real-time PCR. To determine the effect of estrogen on premenopausal expression of RNAseq identifed genes during Ang II infusion we used two models of estrogen signlaing disruption. Both animal wide knockdown of estrogen receptor a and 4-vinylcyclohexene diepoxide (VCD) induction of menopause, significantly altered expression of RNAseq identified genes. To examine the effect of T cell activation on RNAseq gene expression, CD4+ T cells from control and Ang II treated premenopausal and male mice were stimulated in vitro. Sex differences in T cell RNAseq gene expression were associated with sex differences in supernatant concentration of IL10, IL4, and IFNg and renal IL10, IL4, and IL2 content. Conclusions: These estrogen dependent T cell transcriptomic pathways and sex dependent functional differences in T cell cytokine secretion identify novel pathways that may mediate sex specific inflammatory responses during hypertension development.

ORGANISM(S): Mus musculus

PROVIDER: GSE158946 | GEO | 2020/10/03

REPOSITORIES: GEO

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Project description:Gliomas are aggressive primary brain tumors, presenting surgery limitations due to their highly infiltrative potential. The expression of Angiotensin II (Ang II) receptors in human astrocytomas was previously associated with a poor prognosis. Accordingly, this study was undertaken to reveal the molecular mechanisms underlying Ang II actions in gliomas through the transcriptomic analysis of glioma cells exposed to Ang II. C6 glioma cells were treated with Ang II and specific antagonists of AT1 and AT2. Total RNA was isolated at three and six hours intervals and submitted to oligonucleotide microarray protocol. The differentially expressed genes were obtained by paired t-tests with p<0.05 and interpreted using Venn diagrams, functional enrichment and protein interaction network analyses. Validation of microarray results was carried out through qPCR experiments of selected genes. We found a high number of significant genes with low fold changes in gene expression at the time intervals studied. These genes were regulated in a time dependent-manner, with most gene expression changes being exclusive to one of the time intervals evaluated. Our results indicated that blocking AT1 or AT2 changed the expression of genes involved in regulation of transcription, cell cycle, cell proliferation, differentiation, apoptosis, cell adhesion, cell migration, regulation of actin cytoskeleton, protein transport and protein ubiquitination. Additionally, the signaling pathways over-represented by the significant genes were ErbB, mTOR, MAPK, neurotrophin, insulin and Wnt. Finally, interactome analyses revealed hub genes associated with cell proliferation, survival, migration, transport, structural support, neurotrophin pathway, MAPK signaling and Wnt signaling. Taken together, our findings implicate Ang II-transcriptional regulation in glioma progression by means of the modulation of genes participating in protumoral functions. This transcriptome pattern is observed upon Ang II activation of either AT1 or AT2 receptors, thereby highlighting the relevance of both receptor subtypes in glioma progression. Interactome analyses disclosed hub genes regulated by Ang II which may present higher control over their networks. These genes participate in biological functions that could enhance the degree of malignancy in gliomas and thus should be further explored. C6 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 100 Units/ml penicillin and 100 M-BM-5g/ml streptomycin. Cells were seeded in cell culture dishes and incubated at 37M-BM-0C/ 5% CO2 until becoming confluent. Then, these cells were pre-treated (30 minutes) with either AT1 receptor antagonist (Losartan: 10-5M) or AT2 receptor antagonist (PD123319: 10-5M) followed by Ang II treatment (10-7 M) according to the treatment scheme: Group 1 M-bM-^@M-^S control; Group 2 M-bM-^@M-^S cells only treated with Ang II; Group 3 M-bM-^@M-^S cells pre-treated (30 minutes) with Losartan and then treated with Ang II; Group 4 M-bM-^@M-^S cells pre-treated (30 minutes) with PD123319 and then treated with Ang II. To identify which genes were significantly differentially expressed, paired t-tests (p<0.05) were performed in the following comparisons: Ang II x Control (3h); Ang II x Control (6h); Ang II +Los x Ang II (3h); Ang II +Los x Ang II (6h); Ang II +PD123319 x Ang II (3h); Ang II +PD123319 x Ang II (6h).

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Estrogen dependent CD4+ T cell specific transcriptomic pathways identified in premenopausal protection against hypertension

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