Both Alpha and Beta Adrenergic Receptor Expression Is Increased in the Renal Medulla of Spontaneously Hypertensive African Green Monkeys

Abstract

The African Green Monkey (Chlorocebus aethiops sabaeus), the Caribbean vervet, is a highly translational model of spontaneous hypertension (HT). The Caribbean vervet has a very close phylogenetic relationship with humans with an estimated divergence time of ~12 million years ago. Within a cohort of adult animals, 36% (124 of 345) of African Green Monkeys exhibit systolic blood pressures (SBP)> 140 mmHg, as measured by forearm cuff plethysmography. Heart rate is elevated in HT vs. normotensive (NT) animals (121±2 bpm vs. 136±2 bpm, p<0.05) suggesting that sympathetic nerve activity is likely elevated in the HT African Green Monkey that behaviorally maintains upright posture throughout the day and night. This study tested the hypothesis that adrenergic receptor subtypes are upregulated in the renal cortex, outer medulla, and inner medulla of adult male HT African Green Monkeys. Primers were custom designed and evaluated for appropriate specificities and efficiencies (95–105%) for α1a, α1d, α2a, α2c, β1 and β2 adrenoceptors. Gene expression was measured with qRT‐PCR and normalized to RPS32 or RPS13A expression and RQs compared with the Mann‐Whitney U Test. The HT cohort of African Green Monkeys (n=18) averaged SBP of 168.24 ± 7.25mmHg compared with NT animals (n=18) that averaged 96.61 ± 3.20mmHg. Expression of each adrenoceptor subtype was similar in the renal cortex between the two groups. Expression of α1a, α1d, α2a, and α2c genes were increased in the renal outer medulla of HT animals (α1a: NT RQ 1 ± 0.43 vs. HT RQ 2.26 ± 0.50, p<0.05; α1d: NT RQ 1 ± 0.34 vs. HT RQ 2.25 ± 0.32, p<0.05; α2a: NT RQ 1 ± 0.24 vs. HT RQ 1.92 ± 0.19, p<0.05; and α2c: NT RQ 1 ± 0.15 vs HT RQ 1.65 ± 0.15, p<0.05). β1 and β2 adrenergic receptor expression in the outer medulla was also upregulated in HT animals (β1: NT RQ 1 ± 0.24 vs. HT RQ 1.88 ± 0.18, p<0.05; β2: NT RQ 1 ± 0.21 vs HT RQ 1.87 ± 0.24; p<0.05). Expression of adrenergic receptors in the inner medulla of HT animals was similar (p>0.05), with the exception of the β2 adrenergic receptor, which was upregulated in the HT group (NT RQ 1 ± 0.25 vs HT RQ 1.62 ± 0.10, p<0.05). These data suggest that the renal outer medulla of HT African Green Monkey may be sensitized to sympathetic nerve activity via elevated adrenergic receptor gene expression. Thus, subtle changes in renal sympathetic outflow may elicit renal medullary vasoconstriction and sodium retention and contribute to the development of the spontaneous hypertensive phenotype in the African Green Monkey. This study further characterizes a unique non‐human primate model of spontaneous hypertension with genetic, behavioral, and social similarities to humans, which may lead to the identification of novel therapies for the treatment of idiopathic hypertension.