Kidney Week

Abstract: SA-PO755

Dendritic Cell-Specific JAK2 Contributes to Salt-Sensitive Hypertension via the Epithelial Sodium Channel

Session Information

• Hypertension and CVD: Mechanisms
  November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1503 Hypertension and CVD: Mechanisms

Authors

• Saleem, Mohammad, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Mohammad Saleem,

• Aden, Luul, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Luul Aden,

• Pitzer, Ashley Lauren, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ashley Lauren Pitzer,

• Ishimwe, Jeanne A., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Jeanne A. Ishimwe,

• Elijovich, Fernando, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Fernando Elijovich,

• Laffer, Cheryl L., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Cheryl L. Laffer,

• Pakala, Suman, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Suman Pakala,

• Kastner, Paul D., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Paul D. Kastner,

• Kleyman, Thomas R., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Thomas R. Kleyman,

• Kirabo, Annet, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Annet Kirabo,

Background

Salt-sensitivity of blood pressure is an independent predictor for death due to cardiovascular disease. We recently found that the epithelial sodium channel (ENaC) on dendritic cells mediates NADPH oxidase-dependent formation of immunogenic isolevuglandin (IsoLG)-protein adducts leading to inflammation and salt-sensitive hypertension. We hypothesized that expression of JAK2 specifically in antigen presenting myeloid cells contributes to salt-sensitive hypertension in an ENaC dependent mechanism.

Methods

We used both bulk and single cell transcriptome profiling using RNA-Seq analysis in human antigen presenting cells. We also performed molecular and flow cytometric immune phenotyping along with radio telemetry blood pressure and heart rate monitoring in mice with specific deletion of JAK2 in CD11c+ cells (JAK2 KO). To induce salt sensitivity of blood pressure in otherwise salt resistant C57BL/6 mice, L-NAME was given in drinking water for 2 weeks followed by 3 weeks of high salt treatment.

Results

Transcriptomic analyses in human myeloid antigen presenting cells revealed that high salt treatment in vitro and in vivo upregulates genes of the JAK/STAT pathway, and the downstream regulators including the suppressor of cytokine signaling (SOCS) genes. JAK2 KO mice developed blunted hypertension (124.2 vs 137.2 mmHg, SE=3.84, P=0.02) and reduced heart rate compared to the wildtype littermates during L-NAME/high salt treatment. JAK2 KO mice exhibited less infiltration of effector memory T cells (TEM) in kidney and spleen, with profound reduction in inflammatory markers IL-17a and IFN-gamma in CD4⁺ and CD8⁺ T cells in spleen. Moreover, there was less aortic infiltration of CD11c⁺ cells with less expression of CD86, and less production of IsoLGs and IL1-beta in JAK2 KO mice. These mice also exhibited less monocyte/macrophage infiltration in the kidneys and less volume retention in response to high salt-feeding. We also found that salt-induced expression of ENaC subunit g, and serum/glucocorticoid regulated kinase 1 (SGK1) were reduced in the CD11c⁺ cells.

Conclusion

These results indicate that dendritic cell JAK2 plays an important role in salt-sensitive hypertension through an ENaC-dependent mechanism.

Funding

• Other NIH Support