Macrophage Secretion of miR-106b-5p Causes Renin-Dependent Hypertension
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ABSTRACT:
PROVIDER: PRJNA649967 | ENA |
REPOSITORIES: ENA
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Project description:Chronic inflammation is known to contribute to the development of hypertension, but while the role of lymphocytes is well-established, the myeloid lineage, particularly as a possible mediator of renin-mediated hypertension, has not been studied. Vitamin D deficiency has pro-inflammatory consequences in monocytes, and it is linked to renin-mediated hypertension in mice. This prompted us to test the hypothesis that conditional knockout of the vitamin D receptor (VDR) in macrophages (KODMAC) would promote renin-dependent hypertension. We found that lack of macrophage vdr signaling was sufficient to induce high blood pressure (BP) in mice. Recipients of bone marrow from KODMAC mice experienced increased BP via activation of the renal renin-angiotensin system. Conversely BM transplants from mice with intact vdr signaling reduced BP in KODMAC mice by decreasing plasma renin and increasing urinary Na excretion. Deletion of myeloid vdr promotes vascular macrophage infiltration, increasing ROS-mediated scavenging of NO and reducing renal perfusion, resulting in increased plasma renin. Interestingly, deletion of macrophage vdr promotes their infiltration into the JG cell apparatus, regulating JG cell renin production by an unexpected communication between macrophages and JG cells through miR-106b-5p. Induction of macrophage endoplasmic reticulum stress phospho-PERK and CHOP pathways increased miR-106b-5p secretion, the uptake of which into JG cells induced renin production and release by repression of E2f1 and Pde3b transcription factors, constituting a novel mechanism by which inflammation causes hypertension.
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Project description:We generated myeloid cells lacking VDR (KODMAC) by crossing Vdrfl/fl mice with lysosome-M-promoter-driven Cre mice (Lyz2Cre) in the Ldlr-/-background (a model of diet-induced metabolic syndrome), as previously described13 and compared them to Vdrfl/flLdlr-/- littermates (control). Unbiased miRNA expression analyses using media from KODMAC or control peritoneal macrophages identified 361 differentially expressed miRNAs with p<0.05
2020-08-01 | GSE155511 | GEO
Project description: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.
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Project description:Adult beta cells in the pancreas are the sole source of insulin in our body. Beta cell loss or increased demand for insulin, impose metabolic challenges because adult beta cells are generally quiescent and infrequently re-enter the cell division cycle. miR-17-92/106b is a family of proto-oncogene microRNAs, that regulate proliferation in normal tissues and in cancer. Here, we employ mouse genetics to demonstrate a critical role for miR-17-92/106b in glucose homeostasis and in controlling insulin secretion. Mass spectrometry analysis was performed on miR-17-92LoxP/LoxP;106-25-/- MEF lysate, without or with CRE-Adenovirus. miR-17-92LoxP/LoxP;106-25+/+ MEFs with GFP-Adenovirus served as controls. We demonstrate that miR-17-92/106b regulate the adult beta cell mitotic checkpoint and that miR-17-92/106b deficiency results in reduction in beta cell mass in-vivo. Furthermore, protein kinase A (PKA) is a new relevant molecular pathway downstream of miR-17-92/106b in control of adult beta cell division and glucose homeostasis. Therefore, contributes to the understanding of proto-oncogene miRNAs in the normal, untransformed endocrine pancreas, and illustrates new genetic means for regulation of beta cell mitosis and function by non-coding RNAs.
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Project description:MiRNAs have been shown to alter both protein expression and secretion in different cellular contexts. By combining in vitro, in vivo and in silico techniques, we demonstrated that overexpression of pre-miR-1307 reduced the ability of breast cancer cells to induce endothelial cell sprouting and angiogenesis. However, the molecular mechanism behind this and the effect of the individual mature miRNAs derived from pre-miR-1307 on protein secretion and is largely unknown. Here, we overexpressed miR-1307-3p|0, -3p|1 and 5p|0 in MDA-MB-231 breast cancer cells and assessed the impact of miRNA overexpression on protein secretion by Mass Spectrometry. Unsupervised hierarchical clustering revealed a distinct phenotype induced by overexpression of miR-1307-5p|0 compared to the controls and to the 5’isomiRs derived from the 3p-arm. Together, our results suggest different impacts of miR-1307-3p and miR-1307-5p on protein secretion which is in line with our in vitro observation that miR-1307-5p, but not the isomiRs derived from the 3p-arm reduce endothelial cell sprouting in vitro. Hence these data support the hypothesis that miR-1307-5p is at least partly responsible for impaired vasculature in tumors overexpressing pre-miR-1307.
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