1. The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension.
- Author
-
Benson LN, Liu Y, Wang X, Xiong Y, Rhee SW, Guo Y, Deck KS, Mora CJ, Li LX, Huang L, Andrews JT, Qin Z, Hoover RS, Ko B, Williams RM, Heller DA, Jaimes EA, and Mu S
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Disease Models, Animal, Kidney Tubules, Distal metabolism, Kidney Tubules, Distal pathology, Mice, Sodium metabolism, Sodium Chloride Symporters metabolism, Sodium Chloride, Dietary, Desoxycorticosterone Acetate metabolism, Desoxycorticosterone Acetate pharmacology, Hypertension metabolism
- Abstract
Background: Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated., Methods: We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8
+ T cells (CD8T) from hypertensive animals to normotensive animals in in vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. Interferon (IFNγ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis., Results: We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models., Conclusions: Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFNγ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.- Published
- 2022
- Full Text
- View/download PDF