Kidney resident memory CD8 T cells mediate recurrence of salt-sensitive hypertension

Abstract

One of the significant challenges in treating hypertension is insuffcient blood pressure (BP) control and recurring high BP due to high salt intake or cessation of medication. We previously reported that CD8 T cells contribute to the pathogenesis of salt-sensitive hypertension. Notably, while antihypertensive therapy temporarily lowered BP in hypertensive mice, it failed to disrupt T cell residency in the kidneys, and high BP recurred after stopping treatment. Building on these findings, we hypothesize that the establishment of long-living resident memory CD8Ts (CD8Trms) in the kidney is essential in the progression and recurrence of salt-sensitive hypertension. To test this hypothesis, we employed both wild-type (WT) mice and mice with T-cell-specific KO of TGFβRII (Tsp-TGFβRKO), which prevents the formation of resident memory T cells (Trms). Our mouse models of hypertension include the classic DOCA + salt (DOCA) model and an Angiotensin II (Ang II) model simulating the recurrence of hypertension induced by salt memory. In this salt-memory model, the initial BP elevation was induced by a one-week infusion of Ang II. Following recovery and the normalization of blood pressure after removal of Ang II, the mice were subjected to a chronic high salt intake to rechallenge their blood pressure. Throughout the experiments, we continuously recorded blood pressure using radiotelemetry. We isolated and extensively examined T cells from the spleen (representing circulating T cells) and the kidney (Trms) using multicolor flow cytometry. As expected, DOCA treatment induced salt-sensitive hypertension in WT mice, accompanied by a significant expansion of the CD8Trm population within their kidneys. Intriguingly, this population of CD8Trms was notably diminished in the kidneys of DOCA-treated Tsp-TGFβRKO mice. Importantly, mice lacking CD8Trms in their kidneys exhibited attenuated BP elevation upon DOCA treatment. Additionally, in the Ang II-induced salt-memory model, WT mice demonstrated recurring hypertension as they quickly developed hypertension not only during Ang II infusion but also when faced with the high-salt challenge after the resting period. Testing the capability of retaining salt memory in mice unable to develop Trm, we repeated this model in the Tsp-TGFβRII KO mice. Initially, no significant difference was observed in the initial development of hypertension with Ang II or the return to baseline blood pressure during the resting period in Tsp-TGFβRII KO mice compared to WT. However, when challenged with high salt after a resting period, the Tsp-TGFβRII KO mice remained normotensive, while their WT counterparts quickly redeveloped hypertension. Isolation of T cells from the kidney at the end of the model confirmed significant CD8Trm population development in the WT mice, which was absent in the Tsp-TGFβRII KO mice. In summary, our study revealed a critical role of kidney CD8Trms in contributing to salt-sensitive hypertension and conferring the ‘salt memory’ that mediates its recurrence. The key molecules that participate in establishing the kidney CD8Trms represent potential therapeutic targets for developing new medications to manage the progression of hypertension and mitigate its persisting effects. T32 T-SPaT GM150536 (Deck), NIH R01-HL146713 (Mu), AHA 23TPA10764467 (Mu). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.