Systems‐level Multi‐organ Modeling of Transcriptomic Data to Reveal Sex‐specific Shifts in Regulatory Control During the Development of Hypertension

Abstract

Hypertension is a multifactorial disease involving the dysregulation of several organs. The organ‐organ interactions and time course dynamics are yet to be well delineated. We analyzed pathway‐scale gene expression across five organs during the development of hypertension in female Spontaneously Hypertensive rats (SHR), at five time points from early onset (8,10,12 weeks of age) to established hypertension (16 and 24 weeks), and age‐matched normotensive Wistar Kyoto (WKY) rats. We studied the interactions within and across organs by integrating the gene expression analysis with a Hartley Modulating Function based system identification approach to reverse engineer data‐driven dynamic network models of multi‐organ gene regulatory influences. Our results indicate a dynamic dysregulation of gene expression spanning multiple organs over time in female SHR. Adrenal gland showed the most robust gene expression changes across multiple pathways, including the renin angiotensin system and catecholaminergic processes. These changes in the adrenal gland preceded the differential regulation of inflammation‐relevant processes in the kidney. The inferred multi‐organ network model suggests a diminished influence of the differential gene regulation in the central nervous system on the gene expression changes in spleen and lung. This was paralleled by an increased influence of adrenal gene regulation over the gene expression changes in multiple other organs. We compared the results to the available male SHR multi‐organ gene expression analysis and modeling. We found that the gene dysregulation patterns, temporal sequencing and putative organ‐organ influences are distinct to female SHR, highlighting the sex‐specific multi‐organ regulatory processes driving hypertension.