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.
Highlights
Myeloid cells are known mediators of hypertension, but their role in initiating renin-induced hypertension has not been studied
To begin to determine the role of macrophages in the hypertensive phenotype resulting from vitamin D deficiency, we generated myeloid cells lacking vitamin D receptor (VDR) (KODMAC) by crossing Vdrfl/fl mice with lysosome-M-promoter-driven Cre mice (Lyz2Cre) in the Ldlr−/− background, and compared them to Vdrfl/flLdlr−/− littermates
Irradiated KODMAC mice transplanted with bone marrow from other KODMAC (KOD→KOD) or control mice (Con→KOD) demonstrated that restoration of myeloid VDR could prevent hypertension, with 20–28 mmHg lower BP (Fig. 1h) and a 36% reduction in plasma renin (Fig. 1i) after 8 weeks in Con→KOD mice compared to KOD→KOD mice
Summary
Myeloid cells are known mediators of hypertension, but their role in initiating renin-induced hypertension has not been studied. 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. 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. We show that vitamin D-mediated ER stress and subsequent miR-106b-5p secretion from macrophages is sufficient to cause hypertension
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