Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Nat Commun. 2020 Sep 23;11(1):4798. doi: 10.1038/s41467-020-18538-x.
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.
髓系细胞是高血压的已知介质，但它们在引发肾素诱导的高血压中的作用尚未得到研究。维生素 D 缺乏会导致代谢组织中促炎巨噬细胞浸润，并与肾素介导的高血压有关。我们使用髓系维生素 D 受体条件敲除小鼠 (KODMAC) 检验了巨噬细胞中维生素 D 信号受损会导致高血压的假设。这些小鼠由于血管内的巨噬细胞浸润和直接激活肾球旁细胞 (JG) 细胞肾素产生而发展为依赖肾素的高血压。敲除巨噬细胞内质网应激的诱导会增加 miR-106b-5p 的分泌，通过抑制转录因子 E2f1 和 Pde3b 来刺激 JG 细胞肾素产生。此外，在 KODMAC/miR106b 骨髓的野生型受体小鼠中，敲除 miR-106b-5p 可预防 KODMAC 巨噬细胞引起的高血压和 JG 细胞肾素产生，表明这是髓系特异性、miR-106b-5p 依赖性的作用。这些发现证实了受损的维生素 D 受体信号导致巨噬细胞 miR-106b-5p 分泌引起炎症诱导的高血压。
