Blood pressure and the kidney cortex transcriptome response to high-sodium diet challenge in female nonhuman primates

Abstract

Blood pressure (BP) is influenced by genetic variation and sodium intake with sex-specific differences; however, studies to identify renal molecular mechanisms underlying the influence of sodium intake on BP in nonhuman primates (NHP) have focused on males. To address the gap in our understanding of molecular mechanisms regulating BP in female primates, we studied sodium-naïve female baboons (n=7) fed a high sodium (HS) diet for 6 weeks. We hypothesized that in female baboons variation in renal transcriptional networks correlates with variation in BP response to a high sodium diet. BP was continuously measured for 64-hour periods throughout the study by implantable telemetry devices. Sodium intake, blood samples for clinical chemistries, and ultrasound-guided kidney biopsies were collected before and after the HS diet for RNA-Seq and bioinformatic analyses. We found that on the LS diet but not the HS diet, sodium intake and serum 17 beta-estradiol concentration correlated with BP. Furthermore, kidney transcriptomes differed by diet - unbiased weighted gene co-expression network analysis revealed modules of genes correlated with BP on the HS diet but not the LS diet. Our results showed variation in BP on the HS diet correlated with variation in novel kidney gene networks regulated by ESR1 and MYC, i.e., these regulators have not been associated with BP regulation in male humans or rodents. Validation of the mechanisms underlying regulation of BP associated gene networks in female NHP will inform better therapies towards greater precision medicine for women.

Cell-type deconvolution of bulk RNA-Seq from kidney using opensource bioinformatic tools

“…We identified a group of baboons with low degree of relatedness representing diverse genetic backgrounds from the SNPRC colony (Additional File 1 tab S1). We performed a standard workflow for quality filtering of bulk RNA-Seq data prior to comparison of females and males to identify differentially expressed genes (30,32). We assessed pre-alignment total reads, average read length, and average Phred quality score (Fig 1A , 1B, 1C).…”

“…Females were run into individual cages during feeding times. Males were housed individually prior to study start for 6 weeks (29,30,32).…”

“…Daily enrichment was provided by the SNPRC veterinary staff and behavioral staff in accordance with AAALAC, NIH, and USDA guidelines. The KINSHIP program from Pedigree Database System (PEDSYS v. 2.0) was used with the Stevens-Boyce algorithm to calculate kinship coefficients to ensure similar degrees of relatedness among all animals (29)(30)(31).…”

“…Buprenorphine (0.2 mg/kg, SQ) was administered for post-operative pain relief immediately once animals were awake. Buprenorphine (0.2 mg/kg, SQ) was administered as needed 24-48 hours after surgery (29)(30)(31).…”

“…We also provide an example using this method for cell type composition analysis of kidney cortex biopsy samples obtained from female and male baboons. Baboons (Papio hamadryas) are genetically and physiologically similar to humans and have been used to study the role of the kidney in many complex diseases (21)(22)(23)(24)(25)(26)(27)(28)(29)(30). The structures and substructures within the kidney are quite heterogeneous and to date, more than 40 different cell types have been identified among mammals (14,20).…”