Item Details

title

RENAL GENE EXPRESSION UNDERLYING BLOOD PRESSURE REGULATION IN FEMALE PRIMATES

author

Riojas, Angelica

abstract

Hypertension is a complex disease influenced by genetic factors including sex and environmental factors such as sodium intake. Human and rodent studies have revealed sex differences in blood pressure (BP) onset and control with antihypertensive drug therapies. In addition, approximately ninety percent of Americans consume more than the AHA recommended amount of sodium. However, the current clinical guidelines do not offer sex-specific treatment plans for sodium sensitive HT. Baboons are a model for sodium sensitive BP due to their genetic and physiological similarities to humans, including having continuous and heritable BP. Previous studies investigating the impact of genetic variation and sodium intake on BP in baboons to date have focused on males. This work aimed 1) to understand whether there are sex differences in primate BP and kidney cortex transcriptome on a low sodium (LS) diet, and, 2) to determine the renal gene networks regulating BP on a LS and high sodium (HS) diet in female primates. To address the first aim, sodium-naïve female (n=8) and male (n=9) baboons were fed a low-sodium chow diet throughout life prior to and during the study. Blood pressure was continuously monitored by implantable telemetry device over 24-hours at weekly intervals for 12 weeks, and ultrasound-guided kidney biopsies were collected for RNA-Seq. Blood chemistries were also performed. We found that serum 17 beta-estradiol concentration correlated BP in females. BP in males correlated with Na+ intake, blood urea nitrogen, and glucose. Kidney cortex cell type composition in biopsies was consistent between females and males. Sex differences were observed in the kidney transcriptomes by both principal components analysis and weighted gene co-expression network analysis. Network analysis revealed HNF4A, ESR1, ESR2, SMARCA4, TP53, and NR3C1 as BP regulators in males, but no BP regulators were identified in females. To address the second aim, sodium-naïve female baboons (n=7) were fed a LS diet for 6 weeks followed by a HS diet for 6 weeks. At the end of each 6-week diet feeding, sodium intake, serum 17 beta-estradiol, and ultrasound-guided kidney biopsies, and continuous BP were collected. Quality BP measures were obtained over 64-hour continuous recording periods by implantable telemetry devices at weekly intervals for xxx weeks. Na+ intake and serum 17 beta-estradiol concentration correlated with BP on the LS diet. Cell type composition of renal biopsies was consistent among all animals for both diets, but kidney transcriptomes overall differed by diet. Renal biopsy RNA Seq data were analyzed by unbiased weighted gene co-expression network analysis and revealed modules of genes correlated with BP on the HS diet. Network analysis of module genes showed a causal network consisting of 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. Immunohistochemistry of downstream target VEGFA demonstrated protein abundance correlated with blood pressure and sodium intake on a HS diet. These results demonstrated sex differences in sodium naïve primate kidneys and identified novel networks for BP control in males and females. These findings are a first step towards informing better therapies towards the goal of precision medicine for women and men.

subject

Baboon

Genetics

Hypertension

Kidney

Salt-sensitive

WGCNA

contributor

Cox, Laura A (committee chair)

Olivier, Michael (committee member)

South, Andrew (committee member)

Hawkins, Gregory (committee member)

Parks, John (committee member)

date

2022-01-15T09:35:31Z (accessioned)

2023-01-14T09:30:15Z (available)

2022 (issued)

degree

Molecular Medicine and Translational Science (discipline)

embargo

2023-01-14 (terms)

identifier

http://hdl.handle.net/10339/99388 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation