Author:

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, SALT-SENSITIVE HYPERTENSION, OXIDATIVE STRESS, BLOOD-PRESSURE, 1,25-DIHYDROXYVITAMIN D-3, ATHEROSCLEROSIS, INFLAMMATION, CELL, INFILTRATION, ASSOCIATION, RESISTANCE, Animals, Bone Marrow, Bone Marrow Transplantation, Disease Models, Animal, E2F1 Transcription Factor, Endoplasmic Reticulum Stress, Female, Hypertension, Hypertension, Renal, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs, Myeloid Cells, Nephritis, Receptors, Calcitriol, Renin, Vitamin D

Abstract:

Myeloid cells are known mediators of hypertension, but their role in initiating renin-induced hypertension has not been studied. Vitamin D deficiency causes pro-inflammatory macrophage infiltration in metabolic tissues and is linked to renin-mediated hypertension. We tested the hypothesis that impaired vitamin D signaling in macrophages causes hypertension using conditional knockout of the myeloid vitamin D receptor in mice (KODMAC). These mice develop renin-dependent hypertension due to macrophage infiltration of the vasculature and direct activation of renal juxtaglomerular (JG) cell renin production. Induction of endoplasmic reticulum stress in knockout macrophages increases miR-106b-5p secretion, which stimulates JG cell renin production via repression of transcription factors E2f1 and Pde3b. Moreover, in wild-type recipient mice of KODMAC/miR106b-/- bone marrow, knockout of miR-106b-5p prevents the hypertension and JG cell renin production induced by KODMAC macrophages, suggesting myeloid-specific, miR-106b-5p-dependent effects. These findings confirm macrophage miR-106b-5p secretion from impaired vitamin D receptor signaling causes inflammation-induced hypertension.