The IFNγ-PDL1 pathway enhances CD8T-DCT interaction to promote hypertension Journal Article
| Authors: | Benson, L. N.; Liu, Y.; Wang, X.; Xiong, Y.; Rhee, S. W.; Guo, Y.; Deck, K. S.; Mora, C. J.; Li, L. X.; Huang, L.; Andrews, J. T.; Qin, Z.; Hoover, R. S.; Ko, B.; Williams, R. M.; Heller, D. A.; Jaimes, E. A.; Mu, S. |
| Article Title: | The IFNγ-PDL1 pathway enhances CD8T-DCT interaction to promote hypertension |
| 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 (IFN gamma)-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-gamma-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-gamma 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 IFN gamma-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets. |
| Keywords: | interferon; hypertension; inflammation; blood pressure; immunity; lymphocytes; sodium chloride; expression; gamma; activation; pd-l1; cd8(+) t-cells; blood-pressure; salt-sensitive hypertension; tubular epithelial-cells |
| Journal Title: | Circulation Research |
| Volume: | 130 |
| Issue: | 10 |
| ISSN: | 0009-7330 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2022-05-13 |
| Start Page: | 1550 |
| End Page: | 1564 |
| Language: | English |
| ACCESSION: | WOS:000792906000008 |
| DOI: | 10.1161/circresaha.121.320373 |
| PROVIDER: | wos |
| PMCID: | PMC9106883 |
| PUBMED: | 35430873 |
| Notes: | Article -- Source: Wos |
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