Dataset Information

Inhibition of Interleukin 17-A but not Interleukin-17F Signaling Lowers Blood Pressure and Reduces End-organ Inflammation in Angiotensin II-induced Hypertension.

ABSTRACT:

Objectives

To characterize the T cell subsets producing interleukin 17 (IL-17) isoforms A and F in hypertensive kidneys and vessels and determine whether inhibition of IL-17 signaling lowers blood pressure and end-organ damage in a mouse model of hypertension.

Background

T cell derived cytokines play a central role in the pathophysiology of hypertension and contribute to end-organ dysfunction. We previously showed that mice genetically deficient in IL-17A exhibited blunted hypertension and reduced renal and vascular dysfunction in response to angiotensin II (Ang II) infusion. Monoclonal antibodies to IL-17 isoforms or the IL-17 receptor are emerging as novel therapeutics for psoriasis and related autoimmune disorders.

Methods and results

Mice were infused with Ang II for 4 weeks to induce hypertension. Using flow cytometry and intracellular staining, we determined that the primary T cell subsets producing IL-17A and IL-17F in the kidney and aorta are gamma delta (γδ) T cells and CD4+ T helper 17 (T_H17) cells. Monoclonal antibodies were administered twice weekly starting 2 weeks after the onset of Ang II infusion. Antibodies to IL-17A or the IL-17 receptor A subunit (IL-17RA), but not IL-17F, lowered blood pressure by 30 mmHg, attenuated renal and vascular lymphocyte infiltration, and reduced renal transforming growth factor beta (TGFβ) levels (a marker of renal fibrosis) compared to control IgG1 antibodies. Inhibition of IL-17 signaling also blunted the progression of albuminuria.

Conclusions

Monoclonal antibodies to IL-17A or IL-17RA, but not IL-17F, may be a useful adjunct treatment for hypertension and the associated end-organ dysfunction.

SUBMITTER: Saleh MA

PROVIDER: S-EPMC5337944 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundAlthough transplantation of the fecal microbiota from normotensive donors has been shown to have an antihypertensive effect in hypertensive animal models, its effect on blood pressure in patients with hypertension is unclear. This study aimed to assess the effect of washed microbiota transplantation (WMT) from normotensive donors on blood pressure regulation in hypertensive patients.MethodsThe clinical data of consecutive patients treated with washed microbiota transplantation (WMT) were collected retrospectively. The blood pressures of hypertensive patients before and after WMT were compared. The factors influencing the antihypertensive effect of WMT in hypertensive patients and fecal microbial composition of donors and hypertensive patients were also analyzed.ResultsWMT exhibited an antihypertensive effect on blood pressure: the blood pressure at hospital discharge was significantly lower than that at hospital admission (change in systolic blood pressure: -5.09 ± 15.51, P = 0.009; change in diastolic blood pressure: -7.74 ± 10.42, P < 0.001). Hypertensive patients who underwent WMT via the lower gastrointestinal tract (β = -8.308, standard error = 3.856, P = 0.036) and those not taking antihypertensive drugs (β = -8.969, standard error = 4.256, P = 0.040) had a greater decrease in systolic blood pressure, and hypertensive patients not taking antihypertensive drugs also had a greater decrease in diastolic blood pressure (β = -8.637, standard error = 2.861, P = 0.004). After WMT, the Shannon Diversity Index was higher in six of eight hypertensive patients and the microbial composition of post-WMT samples tended to be closer to that of donor samples.ConclusionWMT had a blood pressure-lowering effect in hypertensive patients, especially in those who underwent WMT via the lower gastrointestinal tract and in those not taking antihypertensive drugs. Therefore, modulation of the gut microbiota by WMT may offer a novel approach for hypertension treatment.