Sex Differences in Blood Pressure and the Kidney Cortex Transcriptome in Nonhuman Primates

Reeves

Shade

et al. 2022

Physiological Genomics

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.

Section: Introductionmentioning

confidence: 70%

Section: Ethics Study Design and Data Collectionmentioning

confidence: 99%

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

Reeves

Shade

et al. 2022

Physiological Genomics

Section: Introductionmentioning

confidence: 70%

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

Shade

et al. 2021

Preprint

Self Cite

Blood pressure (BP) is influenced by genetic variation and sodium intake. Ninety percent of Americans consume more than the AHA recommended amount of sodium. Studies on the impact of genetic variation and sodium intake on BP in nonhuman primates (NHP) to date have focused on males. We hypothesized that variation in renal transcriptional networks correlate with BP response to high dietary sodium in female baboons. Sodium-naïve female baboons (n=7) were fed a low-sodium (LS) diet for 6 weeks followed by a high sodium (HS) diet for 6 weeks. Sodium intake, serum 17 betaestradiol, and ultrasound-guided kidney biopsies for RNA-Seq BP were collected at the end of each diet. BP was continuously measured for 64-hour periods throughout the study by implantable telemetry devices. On the LS diet, Na+ intake and serum 17 beta-estradiol concentration correlated with BP.Kidney transcriptomes differed by diet; analysis by unbiased weighted gene co-expression network analysis revealed modules of genes correlated with BP on the HS diet. Cell type composition of renal biopsies was consistent among all animals for both diets. Network analysis of module genes showed causal networks linking hormone receptors, proliferation and differentiation, methylation, hypoxia, insulin and lipid regulation, and inflammation as regulators underlying variation in BP on the HS diet. Our results show variation in BP correlated with novel kidney gene networks with master regulators PPARG and MYC in female baboons on a HS diet. Identification of mechanisms underlying regulators that influence BP will inform better therapies towards greater precision medicine for women.

“…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).…”

Section: Ethics Study Design and Data Collectionmentioning

confidence: 99%

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

Section: Diet and Housingmentioning

confidence: 99%

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

Spradling-Reeves

Christensen

et al. 2023

Preprint

Self Cite

Traditional bulk RNA-Seq pipelines do not assess cell-type composition within heterogeneous tissues. Therefore, it is difficult to determine whether conflicting findings among samples or datasets are the result of biological differences or technical differences due to variation in sample collections. This report provides a user-friendly, open source method to assess cell-type composition in bulk RNA-Seq datasets for heterogeneous tissues using published single cell (sc)RNA-Seq data as a reference. As an example, we apply the method to analysis of kidney cortex bulk RNA-Seq data from female (N=8) and male (N=9) baboons to assess whether observed transcriptome sex differences are biological or technical, i.e., variation due to ultrasound guided biopsy collections. We found cell-type composition was not statistically different in female versus male transcriptomes based on expression of 274 kidney cell-type specific transcripts, indicating differences in gene expression are not due to sampling differences. This method of cell-type composition analysis is recommended for providing rigor in analysis of bulk RNA-Seq datasets from complex tissues. It is clear that with reduced costs, more analyses will be done using scRNA-Seq; however, the approach described here is relevant for data mining and meta analyses of the thousands of bulk RNA-Seq data archived in the NCBI GEO public database.