GSE158946
Estrogen dependent CD4+ T cell specific transcriptomic pathways identified in premenopausal protection against hypertension
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. Overall design: Splenic CD4+ T cell mRNA from premenopausal control and Ang II treated mice (14 days 800 ng/kg/min) (n = 3 mice/group)