Kidney Week

Abstract: SA-PO772

Loss of Serum and Glucocorticoid Kinase 1 (SGK) in T Cells Abrogates Memory T Cell Formation, Hypertension, and End-Organ Damage

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

• Maaliki, Dina, American University of Beirut, Beirut, Lebanon

Dina Maaliki,

• Itani, Maha M., American University of Beirut, Beirut, Lebanon

Maha M. Itani,

• Jarrah, Hala Hachem, American University of Beirut, Beirut, Lebanon

Hala Hachem Jarrah,

• El-Mallah, Carla, American University of Beirut, Beirut, Lebanon

Carla El-Mallah,

• Obeid, Omar, American University of Beirut, Beirut, Lebanon

Omar Obeid,

• Jaffa, Miran A., American University of Beirut, Beirut, Lebanon

Miran A. Jaffa,

• Itani, Hana A., American University of Beirut, Beirut, Lebanon

Hana A. Itani,

Background

NaCl concentrates in tissues over time and activates immune cells including T _H17 cells and dendritic cells, which are known to contribute to hypertension, in a Serum/Glucocorticoid Kinase 1(SGK1)-dependent fashion. In addition to T_H17 cells and dendritic cells, memory T cells play a vital role in hypertension genesis. Long-lived memory cells generate a systemic inflammatory response through mobilization to target organs and release of cytokines. To understand the mechanisms by which memory T cells sense salt, we tested the hypothesis that SGK1, an important intracellular sensor of Na⁺, in T cells is necessary for the formation of memory T cells and their mediation of salt sensitive hypertension and organ damage.

Methods

We employed mice with T cell-specific deletion of SGK1, SGK1^fl/fl x tgCD4^cre mice, and used SGK1^fl/fl mice as controls. To mimic repeated exposure to hypertensive stimuli, we treated mice with L-NAME (0.5mg/ml) in drinking water for 2 weeks, allowed a 2-week washout interval, followed by a high salt(HS) diet (4% NaCl) for 3 weeks.

Results

L-NAME/HS significantly increased blood pressure as well as memory T cell infiltration in the kidney, aorta, and bone marrow of SGK1fl/fl mice, as compared to SGK1^fl/fl x tgCD4^cre mice. SGK1^fl/fl mice also demonstrated caused striking albuminuria, cortical fibrosis, cortical ROS generation and increased renal IFN-γ and NGAL expression after L-NAME/HS. Myography studies demonstrated an impaired relaxation in response to acetylcholine but not sodium nitroprusside in mesenteric arterioles from SGK1^fl/fl mice, but not SGK1^fl/fl x tg CD4^cre mice. T cells were sorted and adoptively transferred from the bone marrow of CD45.2 SGK1^fl/fl x tgCD4^cre mice or SGK1^fl/fl controls that had undergone the L-NAME/HS protocol, to recipient CD45.1 mice. Recipient mice were then fed a HS diet for 3 weeks. Strikingly, mice that had received T cells from SGK1^fl/fl donors exhibited significantly increased blood pressure and renal memory T cell infiltration, compared to mice that had received cells from SGK1^fl/fl x tgCD4^cre donors.

Conclusion

Our data suggest a new therapeutic target to reduce the formation of hypertension-specific memory T cells, which will protect against hypertension and end-organ damage in response to repeated hypertensive stimuli.

Funding

• Other NIH Support