Kidney Week

Abstract: SA-PO756

Resident Renal Dendritic Cells Respond to Salt-Sensitive Hypertension via ToneBP, Leading to Increased Interleukin 6

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

• Yoshigi, Masaaki, University of Utah Health, Salt Lake City, Utah, United States

Masaaki Yoshigi,

• Cunliffe-Koehler, Kennedy, University of Utah Health, Salt Lake City, Utah, United States

Kennedy Cunliffe-Koehler,

• Eaton, Amity F., Harvard Medical School, Boston, Massachusetts, United States

Amity F. Eaton,

• Srinivasan, Harini, University of Utah Health, Salt Lake City, Utah, United States

Harini Srinivasan,

• Brown, Dennis, Harvard Medical School, Boston, Massachusetts, United States

Dennis Brown,

• Battistone, Maria A., Harvard Medical School, Boston, Massachusetts, United States

Maria A. Battistone,

• Wynne, Brandi M., University of Utah Health, Salt Lake City, Utah, United States

Brandi M. Wynne,

Background

During hypertension, dendritic cells (DCs) have been shown to activate immune cells and secrete cytokines, such as IL-6. DCs also form an intricate network within the renal cortex. Tonicity-Responsive Enhancer Binding Protein (ToneBP) is a transcriptional regulator of the cellular response to hypertoncity. ToneBP plays a role in the stress response in immune cells. We hypothesize that rDCs respond to increased sodium and salt-sensitive hypertension (SS HTN) via ToneBP, leading to increased IL-6 levels.

Methods

To test this hypothesis, mice lacking a functional CX₃CR1 chemokine receptor (CX₃CR1-^EGFP+/+) were used. CX₃CR1 is required for DC localization to the kidney; thus these mice have a renal-specific DC-depletion. Mice were subjected to increased dietary salt (HS, 4%) or normal chow, in addition to a SS HTN model; 2 weeks L-NAME followed by 1-2 weeks of wash-out and then HS chow for the remainder of the study. Pro-inflammatory cytokines using meso-scale design (MSD)(n=3-8) in serum samples. Kidney tissue was used to determine IL-6 mRNA and ToneBP levels (n=4).

Results

Renal-dendritic cell depleted mice had a trending increase in ToneBP mRNA expression following HS (2-3weeks), which was significantly increased (2.39 fold change, p<0.0001) during SS HTN. SS HTN rDC-depleted mice had significantly reduced renal ToneBP expression (1.47 fold change, p<0.05) as compared to SS HTN Wt. When looking at IL-6 levels, we observed reductions in renal IL-6 levels (1.5 fold change) in SS HTN rDC-depleted mice compared to SS HTN Wt, with similar trending reductions in serum IL-6 levels.

Conclusion

Here, we show that resident renal DCs may be a primary contributor to the renal osmostic stress response by ToneBP, as shown by the considerable reductions in ToneBP mRNA following SS HTN in rDC-depleted mice. In addition, we observed similar reductions in renal and serum IL-6 levels. These data suggest that during SS HTN, DC-mediated ToneBP may contribute to the pro-inflammatory cytokine responses by innate immune cells.

Funding

• NIDDK Support