Time restricted feeding decreases renal innate immune cells and blood pressure in hypertensive mice

Abstract

Background: Renal innate immune cell accumulation and inflammation are associated with hypertension. Time restricted feeding (TRF) has been reported to decrease inflammation and blood pressure. Whether TRF can decrease blood pressure by decreasing renal innate immune cells in hypertension is unknown.

Methods and results: We determined whether TRF can decrease blood pressure in two separate mouse models of hypertension, N(G)-nitro-L-arginine methyl ester hydrochloride-induced hypertension (LHTN) and salt-sensitive hypertension (SSHTN). Once hypertension was established after 2 days, TRF (12-h food/12-h no food) for 4 weeks significantly decreased systolic blood pressure in both LHTN and SSHTN mice despite no differences in the amount of food eaten or body weight between groups. Activated macrophages and dendritic cells in the kidneys of both LHTN and SSHTN mice were decreased significantly in mice that underwent TRF. This was associated with an improvement in kidney function (decreased serum creatinine, decreased fractional excretion of sodium, and increased creatinine clearance) which achieved significance in LHTN mice and trended towards improvement in SSHTN mice.

Conclusions: Our findings demonstrate that TRF can significantly decrease renal innate immune cells and blood pressure in two mouse models of hypertension.

FIGURE 1

TRF did not alter food consumption, body weight, or urine volume. (a) Average food consumed per mouse per day, (b) body weight at the end of the 4 weeks, and (c) 24-h urine volume at the end of the 4 weeks in LHTN and SSHTN mice that either had ad libitum access to food and water or underwent TRF. Results are expressed as dot plots with mean line or mean ± SEM. n = 8 mice for each LHTN group and n = 6 mice for each SSHTN group. LHTN, L-NAME-induced hypertension; SSHTN, salt-sensitive hypertension; TRF, time restricted feeding; SEM, standard error of mean.

FIGURE 2

TRF significantly blunted blood pressure in hypertensive mice. Weekly systolic blood pressure measures in (a) LHTN and (b) SSHTN mice that either had ad libitum access to food and water or underwent TRF. Blood pressure readings are organized into dot plots representing mice from the (c) LHTN and (d) SSHTN groups. Results are expressed as dot plots with mean ± SEM. n = 8 mice for each LHTN group and n = 6 mice for each SSHTN group. ^∗P < 0.05 compared to the non-TRF group. LHTN, L-NAME-induced hypertension; SSHTN, salt-sensitive hypertension; TRF, time restricted feeding; SEM, standard error of mean.

FIGURE 3

Renal innate immune cells that were significantly altered by TRF. (a) CD45+CD11b+F4/80+CD38+, (b) CD45+CD11b+F4/80+CD64+, (c) CD45+F4/80-CD11c+, (d) CD45+F4/80-CD11c+CD38+, (e) CD45+CD11b^lowCD11c-, and (f) CD45+CD11c+. Results are expressed as dot plots with mean ± SEM. n = 3 mice for each LHTN group and n = 6 mice for each SSHTN group. TRF, time restricted feeding; SEM, standard error of mean.

FIGURE 4

TRF decreased circulating pro-inflammatory cytokines in hypertensive mice. Serum levels of pro-inflammatory cytokines (a) IL-6 and (b) IL-1b in mice with LHTN and SSHTN. Results are expressed as dot plots with mean ± SEM. For IL-6 calculations, n = 4 for each group. For IL-1b calculations, n = 8 for each LHTN group and n = 6 for each SSHTN group. ^∗P < 0.05 compared to the non-TRF group. LHTN, L-NAME-induced hypertension; SSHTN, salt-sensitive hypertension; TRF, time restricted feeding; SEM, standard error of mean.

FIGURE 5

TRF improved renal sodium handling in hypertensive mice. (a) Serum creatinine, (b) fractional excretion of sodium (FENa), and (c) creatinine clearance (CrCl) at the end of the 4 weeks in LHTN and SSHTN mice that either had ad libitum access to food and water or underwent TRF. Results are expressed as dot plots with mean line. n = 8 mice for each LHTN group and n = 6 mice for each SSHTN group. ^∗P < 0.05 compared to the non-TRF group. LHTN, L-NAME-induced hypertension; SSHTN, salt-sensitive hypertension; TRF, time restricted feeding; SEM, standard error of mean.