T Cells Drive Kidney Memory for Hypertension

Background: For decades, it has been known that the kidney contains a pathogenic memory for salt-sensitive hypertension. For example, kidney transplantation may transfer salt sensitivity and high blood pressure from hypertensive donors to normotensive recipients. However, the culprit cells and mechanisms behind this memory of salt sensitivity remain elusive. Our recent findings suggest that during hypertension, CD8+ T cells (CD8Ts) persist long-term within the kidney, potentially acting as a memory population that perpetuates salt retention. Here, we hypothesize that the establishment of kidney resident memory CD8Ts (CD8Trms) generates the memory of salt sensitivity, resulting in chronic progression and recurrence of hypertension. Methods: In this study, we utilized two mouse models of hypertension: a classic DOCA-salt model and a novel Angiotensin-II (Ang II) + high salt rechallenge-induced salt memory model. To investigate the role of Trms in the pathogenesis of salt-sensitive hypertension, we employed T-cell specific TGFβRII KO (mTSP-TGFβR KO) mice, which are deficient in Trm formation, alongside wild-type (WT) controls. Blood pressure in all mice was recorded using biotelemetry, and T cells were analyzed using flow cytometry. Results: In DOCA-salt-treated WT mice, a significant expansion of CD8Trms occurred accompanied by elevated blood pressure. In contrast, mTsp-TGFβR KO mice, which could not develop Trm, exhibited attenuated blood pressure. Testing the recurrence of hypertension, both WT and mTSP-TGFβR KO achieved a similar degree of hypertension during the initial Ang II-salt administration. Intriguingly, only WT mice, with a significant Trm population, showed rapid recurrence of hypertension upon high salt rechallenge. In contrast, mTSP-TGFβR KO mice, lacking Trm development, appeared protected against recurrent hypertension induced by the high salt re-challenge. Flow cytometry confirmed the presence of a substantial CD8Trm population in WT mice, which was absent in mTSP-TGFβR KO mice. Conclusion: In summary, our study elucidates the mechanisms by which immunological memory, through the formation of kidney-resident memory CD8Ts, underpins the kidney’s “memory of salt sensitivity,” leading to lifelong and recurring hypertension. Funding: Other NIH Support - NIH R01-HL146713 (Mu), T32 T-SPaT GM150536 (Deck), Private Foundation Support