Back to Search
Start Over
Myeloid-Specific JAK2 Contributes to Inflammation and Salt Sensitivity of Blood Pressure.
- Source :
-
Circulation research [Circ Res] 2024 Oct 11; Vol. 135 (9), pp. 890-909. Date of Electronic Publication: 2024 Sep 12. - Publication Year :
- 2024
-
Abstract
- Background: Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP.<br />Methods: We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c <superscript>+</superscript> JAK2 knockout mouse model and measured blood pressure with radiotelemetry after N-omega-nitro-L-arginine-methyl ester and a high salt diet treatment. We used flow cytometry for immunophenotyping and measuring cytokine levels. Fluorescence in situ hybridization and immunohistochemistry were performed to spatially visualize the kidney's immune cells and cytokine levels. Echocardiography was performed to assess cardiac function.<br />Results: We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c <superscript>+</superscript> APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acted downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and proinflammatory cytokine IL (interleukin)-6 in renal APCs, which activate T cells and increase production of IL-17A, IL-6, and TNF-α (tumor necrosis factor-alpha).<br />Conclusions: Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.<br />Competing Interests: None.
- Subjects :
- Animals
Humans
Mice
Male
Smad3 Protein metabolism
Smad3 Protein genetics
Inflammation metabolism
Mice, Inbred C57BL
Myeloid Cells metabolism
Myeloid Cells enzymology
Female
Monocytes metabolism
Monocytes drug effects
Janus Kinase 2 metabolism
Janus Kinase 2 genetics
Sodium Chloride, Dietary adverse effects
Mice, Knockout
Blood Pressure
STAT3 Transcription Factor metabolism
Hypertension metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 135
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 39263750
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.124.323595