SPARC: Time Series Transcriptomic Analysis of the Nucleus of the Solitary Tract During the Development of Hypertension

Abstract

Essential hypertension affects millions of people and is known have a neurogenic component where regions in the brain and brainstem involved in the autonomic nervous system govern the regulation of blood pressure set point. While some work has been done to profile gene expression levels in the nucleus of the solitary tract (NTS) in males, to date no work has specifically looked at how gene expression changes in the NTS drive hypertension development in females. We have conducted a time series mRNA profiling analysis in female spontaneously hypertensive rats (SHR) in comparison to wild type Wistar Kyoto (WKY) allowing us to compare and contrast the results with previously obtained data in males. Rats were sacrificed over the development of and during chronic hypertension at 8, 12, 16, and 24 weeks of age and brainstems were removed and stored in OCT. Brainstems were sectioned on a cryostat and the NTS was extracted using a micropunch. Total RNA was extracted and samples were submitted for RNAseq. We used a data analysis approach focusing on comparative pattern counts (COMPACT) to exhaustively identify the dominant and subtle differential expression patterns (Kuttippurathu et al., BMC Genomics, 2016). Over 2000 genes that show both strain and age dependent differential expression were examined further to interrogate differences in expression patterns between SHR and WKY. Broad analysis reveals that genes involved in the adaptive immune response are differentially regulated in the SHR compared to WKY. Using COMPACT to examine specific patterns, we found that expression levels of many genes involved in transport and secretion of catecholamines do not change over time in WKY but are specifically downregulated in SHR before the onset of hypertension at 8 weeks of age. Interestingly, pathways such as arachidonic acid metabolism that have been implicated in hypertension development in males did not show significant differences between SHR and WKY in females. These results provide valuable insight into the regulatory networks governing hypertension development in females and allows us to compare and contrast this to what is known in males.Support or Funding InformationSupported by the NIH Common Fund SPARC Program award OT2 OD023848 and NIH NHLBI Multiscale Modeling award U01 HL133360.