Establishment of resident memory T cells anchors hypertension in the kidney

Hypertension affects over half of American adults and remains a leading cause of cardiovascular disease and mortality. Despite significant advances in antihypertensives, hypertension often recurs if medication is discontinued. This study aims to identify the underlying cause of this “hypertension memory” and explore potential avenues for a cure. Kidney transplantation studies have long shown that the kidneys retain a memory of hypertension, but the specific perpetrator cells have remained undefined. Recently, we observed the persistence of CD8 + T cells (CD8Ts) in the kidney during hypertension, potentially representing a memory population that drives the recurrence of hypertension. Here, we hypothesize that a resident memory CD8T (CD8Trm) population within the kidney drives the chronic progression and recurrence of hypertension. To test this, we used the classic DOCA-salt model and a high-salt rechallenge after paused hypertension model to assess the impact of CD8Trms on hypertension progression and recurrence. We employed Trm-deficient (Tsp-TGFβR-KO) mice and wild-type (WT) controls. T-cell populations were characterized using flow cytometry, and blood pressure was monitored via biotelemetry. Ex vivo studies on WT and TGFβR-KO CD8Ts further confirmed the stimuli leading to CD8Trm development. Our results show a significant expansion of CD8Trm in the kidneys of DOCA-salt-treated WT mice. In contrast, Tsp-TGFβR-KO mice with the same treatment failed to develop CD8Trms, exhibiting attenuated blood pressure. In the recurrent hypertension study, Ang II was administered to both WT and Tsp-TGFβR-KO mice for a limited period before resting and rechallenging them with high salt intake. Both groups exhibited similar initial hypertension during the Ang II administration. However, only WT mice, which developed a substantial CD8Trm population in the kidneys, experienced a rapid return of hypertension following the high salt challenge after resting and blood pressure normalization. Tsp-TGFβR-KO mice, unable to form CD8Trms, were protected from the recurrence of hypertension. As a mechanism underlying the establishment of CD8Trms in hypertensive kidneys, our previous work noted the requirement of ATP in activating CD8Ts through P2X7. Intriguingly, flow cytometry revealed that the CD8Trm population within the kidney had greater P2X7 expression than non-memory populations throughout the various hypertension models. Ex vivo ATP treatment of WT CD8Ts confirmed that ATP alone can induce a resident memory phenotype, with further potentiation when TGFβ is added. In summary, a novel, long-lived CD8Trm population develops in the kidneys during the onset of hypertension. Removal of this population limits hypertension progression and prevents recurrence, suggesting that CD8Trms are key players in the chronicity and recurrence of hypertension. NIH F31HL175932 (Deck)AHA 24PRE1198737 (Deck)NIH T32 T-SPaT GM150536 (Deck)NIH R01-HL146713 (Mu)AHA 23TPA1076467(Mu) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.