Macrophage secretion of miR-106b-5p causes renin-dependent hypertension

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.

Vitamin D and Cardiovascular Disease: Current Evidence and Future Perspectives

“…Moreover, vitamin D has been shown to induce angiotensin-converting enzyme 2 expression, the enzyme that cleaves angiotensin II to angiotensin 1–7, further counteracting the excess of angiotensin II and, hence, promoting the anti-fibrotic, anti-inflammatory, and anti-hypertensive functions of angiotensin 1–7 [ 19 , 20 ]. Lastly, immune cells that lack VDR have been reported to directly impact on the secretion of miR-106b-5p, which, in turn, may increase renin production by acting on juxtaglomerular cells, thus suggesting the role of inflammation as the cause of renin-driven hypertension [ 21 ].…”

Association of Serum 25-Hydroxyvitamin D Concentrations With All-Cause and Cause-Specific Mortality Among Adult Patients With Existing Cardiovascular Disease

“…In the blood vessels, vitamin D may modulate vascular tone via regulation of calcium influx and stimulation of nitric oxide production in smooth muscle cells ( 38 , 39 ). In addition, it also exhibits anti-inflammatory actions, inhibition of foam cell formation, and reduction of thrombogenicity and vascular calcifications ( 39 , 40 ). Vitamin D deficiency accelerates CAD progression by increasing karyopherin α4 and nuclear factor kappa beta levels ( 41 ).…”

Interleukin-1β in Multifactorial Hypertension: Inflammation, Vascular Smooth Muscle Cell and Extracellular Matrix Remodeling, and Non-Coding RNA Regulation

“…Given that inflammation is a common factor in vascular pathologies, considerable research linking ncRNAs to the inflammatory responses involved in hypertension has been established [60][61][62]. Consistent with this idea, several studies have identified hypertension-related miRNAs such as miR-106b-5p, microRNA-124, and miR-129, which possibly influence hypertension by modulating inflammation [63][64][65][66][67]. Based on the high relevance and association of IL-1β to hypertension, recent studies have led to the discovery of several ncRNAs that target this gene.…”