Kidney-resident memory CD8+ T cells promote hypertension and memorize salt sensitivity. - Kidney-resident memory CD8+ T cells promote hypertension and memorize salt sensitivity. Abstract: An estimated 116 million adult Americans suffer from hypertension, a leading contributor to cardiovascular mortality in the United States. Despite the development of many classes of antihypertensive drugs, only 23.9 million patients obtain effective blood pressure control, implying gaps in our understanding of the complex pathogenesis of hypertension. In recent years, immune cells, specifically CD8+ T cells (CD8Ts), have been implicated in the onset of hypertension. Studies from our group tied CD8Ts directly to aberrant sodium retention within the kidney, beginning with the activation of CD8Ts via purinergic receptor P2X7-mediated calcium influx, resulting in increased production of IFNγ, which enhances the direct interaction between CD8Ts and distal renal tubules, leading to sodium chloride cotransporter (NCC)-mediated excessive salt retention, thereby promoting hypertension. An intriguing discovery in our study is that although antihypertensive treatment temporarily lowered BP in hypertensive animals, it failed to disrupt T cell residency in the kidneys, and salt-sensitive hypertension resurges after ceasing treatment. These findings raise the possibility that a continued adaptive immune response to an initial BP elevation may contribute to the ‘memory of salt sensitivity’ within the kidneys. We hypothesize that the P2X7-TGFβ axis establishes long-term residency of kidney CD8Trms, which exacerbates salt retention and instills “salt memory” of hypertension. First, we aim to determine the critical role of TGFβ signaling in forming kidney-CD8Trms and their impact on the progression of salt- sensitive hypertension. Next, we will define the impact of kidney-CD8Trms on ‘salt memory’ in the kidney and the subsequent recurrence of salt-sensitive hypertension. By establishing long-term CD8T residence through kidney Trms, this study will provide a mechanism behind the longevity of hypertension and identify a resident immune cell population in the kidney that confers the ‘salt memory’ contributing to the progression and recurrence of hypertension.
