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MRNA- and RISC-sequencing of miR-106b-transfected juxtaglomerular (JG) cells

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE117704 | GEO | 2020/07/06

REPOSITORIES: GEO

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Project description:Heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2 plays a pivotal role in vitamin D receptor (VDR) signaling by acting as a vitamin D response element (VDRE)-binding protein (VDRE-BP). Transcriptional regulation by active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) involves occupancy of VDRE by VDRE-BP or 1,25(OH)2D3 bound-VDR. This relationship is disrupted by over-expression of VDRE-BP and can cause a form of human hereditary vitamin D-resistant rickets (HVDRR). DNA array analyses using B-cells from an HVDRR patient and matched control defined a sub-cluster of genes where 1,25(OH)2D3-regulated transcription was abrogated by over-expression of VDRE-BP. Amongst these, the DNA-damage-inducible transcript 4 (DDIT4), an inhibitor of mammalian target of rapamycin (mTOR) signaling, was also induced by 1,25(OH)2D3 in human osteoblasts. Chromatin immunoprecipitation using 1,25(OH)2D3-treated osteoblasts confirmed that liganded VDR and VDRE-BP compete for binding to the proximal promoter of the DDIT4 gene in a similar fashion to other known 1,25(OH)2D3-target genes. Treatment of osteoblasts with 1,25(OH)2D3 induced DDIT4 expression and suppressed phosphorylated S6K1T389 protein (a downstream target of mTOR). The functional importance of this for 1,25(OH)2D3 responses in osteoblasts was underlined by the fact that siRNA knockdown of DDIT4 expression suppressed antiproliferative and cell growth responses to 1,25(OH)2D3. These data confirm that VDRE-BP is required for normal 1,25(OH)2D3-mediated transcription and cell function in osteoblasts. Conversely over-expression of VDRE-BP exerts a dominant-negative effect on transcription of 1,25(OH)2D3-target genes. Characterization of VDRE-BP action in 1,25(OH)2D3-treated osteoblasts highlights an entirely novel role for vitamin D as a regulator of mTOR – a known ‘master regulator’ of cell function. We performed gene expression microarray analysis in HVDRR EBV-transformed B-cells and control cells in the presence or absence of vitamin D.

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MRNA- and RISC-sequencing of miR-106b-transfected juxtaglomerular (JG) cells

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