Neuroinflammation and Age‐Dependent Salt‐Sensitive Hypertension

Abstract

AimNormal aging and elevated dietary sodium intake have both been identified as contributors to hypertension (HTN). Further, recent data from multiple animal models suggest a role of central inflammation in HTN. Therefore, we speculate that central inflammation plays a role in age‐related salt‐sensitive HTN.MethodsMale Sprague‐Dawley rats aged 3, 8, and 16 months (mo) old were randomly assigned to a normal salt (NS; 0.6% NaCl) or high salt (HS; 4% NaCl) diet for 21 days (n=4–6/group). In a subset of animals (n=6/group) MAP was assessed via femoral artery cannulation. Sympathetic tone was assessed via renal norepinephrine (NE) measured by ELISA on day 21 in a subset of animals (n=6/group). Additional groups of rats were sacrificed via transcardial perfusion using phosphate‐buffered saline and 4% paraformaldehyde (PFA). Brains were extracted and fixed in 4% PFA and 30% sucrose. Immunohistochemistry was performed for markers of microglial (CD11b/c) and astrocyte activation (GFAP) in the paraventricular nucleus (PVN) of the hypothalamus, and assessed using ImageJ software.ResultsWhen fed a NS diet, male rats exhibit age‐dependent HTN (MAP [mmHg] 3 mo 124 ± 2 vs. 8 mo 135 ± 4 vs 16 mo 149 ± 3, p<0.05). When fed a 21‐day HS diet, male rats develop salt‐sensitivite HTN (MAP [mmHg] 3 mo 126 ± 3 vs. 8 mo 143 ± 5 vs. 16 mo 169 ± 1, p<0.5). Aged rats display elevated levels of renal NE, with impaired HS‐evoked suppression of sympathetic tone (renal NE content [pg/mg] 3 mo NS 612 ± 36 vs HS 368 ± 32; 8 mo NS 835 ± 48 vs HS 722 ± 44, p<0.05; 16 mo HS 974 ± 13 vs NS 1019 ± 34, ns). There was no statistical difference between branching complexities on trend lines from Sholl analysis of microglia in all groups. On a NS diet, there is no change in astrocytic density in the PVN with age, (total astrocyte % tissue density: 3 mo 41.58 ± 6.00% vs. 8 mo 43.58 ± 3.65% vs. 16 mo 47.18 ± 3.76%, ns). In 3 mo and 8 mo rats, which do not get salt‐sensitive HTN, there is a significant increase in the activation of astrocytes in the PVN when fed a high salt diet (total astrocyte % tissue density: 3 mo NS 41.58 ± 6.00% vs. 3 mo HS 56.66 ± 4.51%, p<0.05; 8 mo NS 43.58 ± 3.65% vs. 8 mo HS 58.28 ± 2.63%, p<0.05). Sixteen month old rats, which become salt‐sensitive and hypertensive with age, exhibit a failure to increase PVN astrocyte levels on a high salt diet (total astrocyte % tissue density: NS 47.18 ± 3.76% vs. HS 50.66 ± 5.01%).ConclusionsMale Sprague‐Dawley rats become hypertensive and salt‐sensitive with age. On a NS diet, inflammation does not play a role in age‐dependent HTN. However, inflammation plays a role in the salt‐sensitivity of blood pressure mediated by astrocyte reactivity. Our findings propose that with age, PVN astrocytes express a loss of a protective mechanism when challenged with a high salt diet.Support or Funding InformationR01 AG062515, R01 HL139867, R01 HL141406, and R56 AG057687 to RDW