Renal Denervation Abolishes the Age-Dependent Increase in Blood Pressure in Female Intrauterine Growth-Restricted Rats at 12 Months of Age

Abstract

Perinatal insults program sex differences in blood pressure, with males more susceptible than females. Aging may augment developmental programming of chronic disease, but the mechanisms involved are not clear. We previously reported that female growth-restricted offspring are normotensive after puberty. Therefore, we tested the hypothesis that age increases susceptibility to hypertension in female growth-restricted offspring. Blood pressure remained similar at 6 months of age; however, blood pressure was significantly elevated in female growth-restricted offspring relative to control by 12 months of age (137±3 versus 117±4 mmHg, P<0.01; respectively). Body weight did not differ at 6 or 12 months of age; however, total fat mass and visceral fat were significantly increased at 12 months in female growth-restricted offspring (P<0.05 versus control). Glomerular filtration rate remained normal, yet renal vascular resistance was increased at 12 months of age in female growth-restricted offspring (P<0.05 versus control). Plasma leptin, which can increase sympathetic nerve activity, did not differ at 6 months, but was increased at 12 months of age in female growth-restricted offspring (P<0.05 versus control). Due to the age-dependent increase in leptin, we hypothesized that the renal nerves may contribute to the age-dependent increase in blood pressure. Bilateral renal denervation abolished the elevated blood pressure in female growth-restricted offspring normalizing it relative to denervated female control offspring. Thus, these data indicate that age induces an increase in visceral fat and circulating leptin associated with a significant increase in blood pressure in female growth-restricted offspring with the renal nerves serving as an underlying mechanism.

Accelerated age-related decline in renal and vascular function in female rats following early-life growth restriction

“…In the IUGR LPD females, it is possible that the initial congenital deficit combined with aging has markedly depleted renal functional reserve and, thus, counteracted the beneficial hormonal effects of circulating estrogen. In support of this idea, a congenital deficit in nephron number has been linked to an age-related decline in renal function in females in other animal programming models [including placental insufficiency (24,38), fetal uninephrectomy (54), and maternal nicotine (55)]. It has been suggested that kidneys with fewer nephrons are more sensitive to some stimuli (ANG II, renal ischemia reperfusion injury), which may increase their vulnerability to renal injury (23).…”

Mechanisms responsible for postmenopausal hypertension in a rat model: Roles of the renal sympathetic nervous system and the renin-angiotensin system

“…In other studies in females, Intapad and colleagues found similar reductions in renal norepinephrine content after bilateral renal denervation in controls (213.9 ± 18.9 pg/mg vs. 30.2 ± 7.5 pg/mg protein) and in adult intrauterine growth‐restricted females (182 ± 5.9 vs. 29.9 ± 7.3 pg/mg protein) (Intapad et al. 2013). Although these colleagues are in our university, their renal norepinephrine levels were measured at Vanderbilt and ours were measured at the Medical College of Wisconsin.…”

Preterm Birth and Hypertension Risk

“…60 Sympathetic nerve activity contributes to blood pressure maintenance, to the elevation in blood pressure in situations of overactivation (or impaired counterregulatory mechanisms) in many forms of chronic hypertension, and after deleterious perinatal conditions (such as IUGR) in both humans and experimental models. [61][62][63] Sympathetic nerve activity can also be activated by chronic inflammation (including through inflammatory cytokines secreted by adipose tissue) and increased expression of the RAS. 64 In infants born preterm, the sympathetic system is overactivated, and parasympathetic nervous system tone is deficient.…”