Investigating new therapeutic opportunities for hypertension through transcriptomic and proteomic analysis of the kidney renin-angiotensin system

Objective: We systematically characterised the expression of all renin-angiotensin system (RAS) genes in the human kidney and searched in silico for new pharmacological therapeutic opportunities to modify RAS. Design and method: We compiled data from open access resources to characterise all components of the RAS pathway. We used transcriptomic profiles of 73 human kidney tissues from the Genotype-Tissue Expression Project, integrated genome-wide DNA genotypes and RNA-sequencing-derived transcriptome profiles of 478 human kidneys from Human Kidney Tissue Resource and, kidney tissue proteomics from 72 samples recruited by Clinical Proteomic Tumour Analysis Consortium. Additionally, we used an independent single-cell RNA sequencing data and gene expression datasets curated from the Kidney Precision Medicine Project (KPMP) and Enrichr (web-based enrichment analysis tool). Lastly, we integrated the Connectivity Map and Drug Gene Interaction Database to identify drug repurposing opportunities for treatment of hypertension targeting the RAS genes. Results: We identified 37 genes encoding components of the RAS pathway with measurable expression in human kidney tissue. 15% of these gene-pairs demonstrated a positive (r>0.5) correlation in kidney expression most consistent with a functionally integrated network of interacting molecules. Angiotensinogen (AGT), the key component of the pathway - showed the highest level of mRNA expression in the liver, and we demonstrated that its hepatic mRNA expression correlates most strongly with its mRNA expression in the kidney (r = 0.71, P = 2.60e-06). Expression levels of mRNA for 92% of RAS genes correlated positively with their protein abundance in the kidney, where renin had the strongest positive correlation (r = 0.64, P<0.01). Enrichr and KPMP revealed that RAS gene expression was enriched in mesangial and epithelial cell types. Existing genetic evidence for correlation between glutamyl aminopeptidase (ENPEP) and systolic blood pressure might relate to its capacity to generate angiotensin III acting on dilator angiotensin II type 2 receptors. This raises potential repurposing opportunities for ENPEP inhibitors like firibastat and tosedostat for the treatment of hypertension. Conclusions: Collectively, this study confirmed synchronized expression of RAS genes in the kidney at both mRNA and protein levels and identified new therapeutic opportunities for treatment of hypertension, through drug repurposing.