Targeting CD8+ T cell responses and metabolism in hypertension therapy
Summary
Hypertension is a leading cause of cardiovascular disease, which affects more than one billion people worldwide. Although many drug families are used to treat hypertension, only fewer than 50% of patients achieve blood pressure control. Thus, it is important to identify unknown mechanisms of hypertension and design improved medications for its treatment. Recent years, growing body of evidence revealed a pivotal role of immune cells, in particular T cells, in the pathogenesis of hypertension. We have demonstrated that activated CD8+ T cells (CD8Ts) stimulate renal tubules to excess salt retention, thereby contributing to the development of hypertension. However, it has become clear that CD8Ts are remarkably diverse in phenotype and function. The atlas of heterogeneity of CD8Ts and the underlying mechanisms that regulate the activation of those cells in hypertensive kidneys are virtually unknown. Thus, these knowledge are necessary for developing novel therapeutics for the future treatment of hypertension.
Cellular metabolism is essential for activation and differentiation of CD8Ts. Moreover, enhanced activation of CD8Ts are observed in both hypertensive human and animals, but the mechanisms of T cell activation in hypertension remain to be investigated. No previous reports have linked metabolic activities to the functions of CD8Ts in the hypertensive kidneys. Here, we hypothesize that a unique activation pattern of CD8Ts and their metabolic states in the kidney contribute to the pathogenesis of hypertension. We will utilize multi-omics approaches to address our hypothesis and two specific aims are proposed accordingly:
Aim 1: Identify the phenotype and effector functions of CD8Ts in the hypertensive kidneys. We will employ single cell RNAseq to analyze the phenotypic and functional heterogeneity of CD8Ts in the kidneys of DOCA-salt-treated hypertensive mice and sham normotensive mice. Multi-color flow cytometry will be used to validate cell surface and intracellular biomarkers of pathologic CD8Ts, and the pathophysiologic role of these cells will be elucidated by T cell adoptive transfer experiments.
Aim 2: Determine the proteomes and metabolic status of CD8Ts in the hypertensive kidneys. Intrinsic metabolism is central for T cell activation and is tightly linked to their function. In this aim we intend to characterize the metabolic network in CD8Ts in blood and the kidneys of hypertensive mice and normotensive mice using quantitative proteomics analysis. Metabolic alterations in CD8Ts will be further validated by real-time extracellular flux analysis (Seahorse). Furthermore, we will infuse metabolic activated T cells into recipient control mice to verify the effects of metabolic activation in causing T cell-infiltration into the kidneys and developing hypertension.
This collaborative study represents a new conceptual framework for how CD8Ts promote hypertension and will be carried out by three PIs and one trainee from two departments in UAMS with expertise in hypertension and renal physiology (Mu, Pharm&Tox), T cell biology (Li, MBIM) and immunometabolism (Huang, MBIM). Our multidisciplinary expertise and state-of-art approaches will ensure successful completion of this project. We envision that identification of CD8+ T cell biomarkers and metabolic states in the hypertensive kidney will reveal new targets for immune-related therapeutics for treating hypertension.
Researchers:
- Shengyu Mu (Author)
- Lin-Xi Li
- Lu Huang
- Lance Benson