Sex Differences in Blood Pressure and Renal Nitric Oxide Bioavailability, Oxidative Stress, and Inflammation in Rodents Exposed to a Low Resource Environment

Background: Adverse childhood experiences (ACEs) are traumatic events, such as poverty, that occur before the age of 18. ACEs affect ~60% of all adults in the United States and is a major risk factor for the development of hypertension (HTN). Multiple clinical and animal studies observe an increase in blood pressure (BP) for humans and rodents that have experienced an ACE or early life stressor (ELS) with sex differences. The mechanisms that link ELS and HTN are unknown, especially in rodents exposed to an impoverished environment. To simulate childhood poverty, we used the limited bedding and nesting (LBN) rodent model, which reduces the nesting and bedding material by ~80% during weaning. To investigate the possible causes of HTN in ELS rodents as adults, we examined renal nitric oxide (NO) bioavailability, oxidative stress (OS), and inflammation in the kidneys. We hypothesize LBN males (M) in adulthood will have elevated BP, with decreased renal NO bioavailability, and increased renal OS and inflammation. LBN females (F) will display no changes in adulthood. Methods: Rats were divided into 4 groups by sex and treatment: LBN M (n=6), LBN F (n=8), CON M (n=7), and CON F (n=8). At 17 weeks of age (adulthood), BP was recorded, and kidney cortex tissue was examined for NO bioavailability via nitrate and nitrite (NOx) concentrations, antioxidant capacity (AC), and 8-isoprostanes (marker of OS), pro-inflammatory cytokines (IL-17 and TNF-α), and anti-inflammatory cytokines (IL-10 and IL-6) by colorimetric assays. Results: LBN M had an increase in BP vs CON M (128±4 vs 110±4 mmHg, p<0.001), while LBN F and CON F showed no difference. LBN rats, regardless of sex, displayed a decrease in NOx production, with LBN M displaying a 2-fold decrease in comparison to CON M (56±9 vs 102±14 uM/mg protein, p<0.05). 8-isoprostane levels were reduced in F compared to M, despite treatment (*p<0.05). There was no difference in 8-isoprostanes between treatment in each sex. However, LBN M had a 2-fold decrease in renal AC vs CON M (233±14 vs 442±12 mM Trolox/mg protein, p<0.0001) and no change was observed in LBN F vs CON F. Renal IL-17 and TNF-α did not change amongst the groups, but IL-10 was reduced by 27% (6415±659 vs 8871±1409 mg/mL/mg protein, ns) and IL-6 was reduced by 30% (3710±366 vs 5325±920 mg/mL/mg protein, ns) in LBN M vs CON M. Moreover, IL-6 was reduced by 50% in LBN M vs LBN F (3710±366 vs 7543±1117 mg/mL/mg protein, p=0.015). Conclusion: In summary, LBN M developed HTN in adulthood, while LBN F did not. The decrease in renal NO bioavailability and increase in renal OS may contribute to BP elevation observed in LBN M. To our surprise, there was no increase in renal pro-inflammatory cytokines in LBN M. However, there was trending and significant decreases in the anti-inflammatory cytokines (IL-10 and IL-6) in LBN M, overall suggesting a pro-inflammatory state in the kidneys due to a reduction in anti-inflammatory cytokines. In LBN F, there were no differences in BP, NO bioavailability, OS, and inflammation in adulthood. Future studies will explore the protective mechanisms in the kidney and BP regulation in F exposed to LBN treatment. This study provides insights into the sex differences in BP and renal responses to an ELS in rodents that mirrors childhood poverty. Childhood poverty is a major public health concern. Understanding the development and pathology of HTN induced by ACEs, along with molecular changes in the kidney may help to alleviate HTN. This research was supported by start-up funds and the American Heart Association Early Career Development Award [AHA 18CDA34110264 (Cunningham)] This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.