A Decrease in Tregs Exacerbates DOCA‐Salt Hypertension and Renal Injury in Female Rats

Abstract

BackgroundT regulatory cells (Tregs) have previously been shown to protect against increases in blood pressure (BP) in male experimental models of hypertension, however less is known regarding the role of Tregs in BP control in females. Our lab has previously reported that there is a sex difference in the renal T cell profile in DOCA, where DOCA results in a decrease in Tregs in males while females maintain their Tregs. The current study tested the hypothesis that Treg maintenance attenuates the increase in blood pressure (BP) to DOCA‐salt in females.MethodsFemale (n=4–7) 13‐week‐old Sprague Dawley rats underwent an uninephrectomy followed by the implantation of a time release 200mg Deoxycorticosterone Acetate (DOCA) pellet and 0.9% saline to drink ad libitum. Rats were then randomized to receive a vehicle or anti‐CD25 injection (IP 250 μg/week) weekly for 3 weeks and BP was measured by telemetry. 24‐hour urinary protein excretion was measured via Bradford Assay at baseline and weekly thereafter for the duration of the study. At the end of the study, kidneys were isolated for flow cytometric analysis of T cells and a terminal plasma sample was collected to measure the kidney injury marker Tim1/Kim1.ResultsAnti‐CD25 injections in DOCA hypertensive females significantly decreased renal (4.2 ± 0.6 vs. 6 ± 0.7; p=0.03) and circulating Tregs compared to DOCA alone (3.6 ± 0.5 vs. 5.5 ± .6 p=0.05). 3 weeks of DOCA‐salt treatment significantly increased BP (101 ± 3 to 160 ± 5; p=<.0001), and decreasing Tregs exacerbated the DOCA‐salt induced increase in BP (109 ± 1 to 188 ± 4; p=0.002). We calculated area under the curve for each BP tracing, and the overall BP load in the rats treated with anti‐CD25 was significantly greater than in rats with DOCA‐salt alone (3327 ± 37 vs. 3662 ± 39; p=0.033). DOCA‐salt also increased urinary protein excretion from baseline to week 3 (3 mg/day ± 0.4 to 34 mg/day ± 9; p=0.01) and this increase was exacerbated with anti‐CD25 treatment (2 mg/day ± 0.5 to 86 mg/day ± 17; p=0.003). Tim1/Kim1 was also increased in DOCA hypertensive females compared to uninephrectomized controls, and this increase was greater in rats treated with anti‐CD25 (control: 292 ± 25 pg/ml; DOCA: 415 ± 57pg/ml; DOCA+anti‐CD25: 589 ± 105; p=0.04).DiscussionOur data suggests that the maintenance of Tregs in DOCA‐salt hypertensive females attenuates increases in BP and renal injury. Future studies will determine if this effect if mediated by the anti‐inflammatory and anti‐hypertensive effects of IL‐10.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.