Metabolic Rewiring of T Cells Bridges Diabetes to Hypertension

About This Grant

PROJECT SUMMARY / ABSTRACT Metabolic syndrome persists as a leading cause of morbidity and mortality among adults in the United States. Specifically, the co-existence of diabetes and hypertension, hallmark components of metabolic syndrome, stand as primary contributors to cardiovascular disease and subsequent mortality. Thus, it is important to identify the pathogenic connection between diabetes and hypertension. Recent research has shed light on the involvement of immune cells, particularly T cells, in the pathogenesis of diabetes and hypertension, suggesting a shared underlying mechanism. However, the precise mechanisms by which immune dysregulation associated with diabetes contributes to hypertension are not fully understood. Here, we delve into the immune-metabolic crosstalk underlying the progression from diabetes to hypertension, employing a high-fat diet-induced type 2 diabetes mouse model. Central to our investigation is the role of T cells, specifically CD8 T cells, in the crosstalk between two diseases. We focus on two key components of diabetes implicated in T-cell activation: ATP and insulin. Elevated ATP levels, acting through the P2X7 receptor, stimulate CD8 T cell activation and cytokine production, promoting the development of hypertension. Moreover, hyperinsulinemia induces ATP release from T cells through the insulin receptor pathway, potentially sustaining chronic diabetic T cell activation. Our research aims are structured around three key objectives: 1) to examine the impact of ATP-P2X7 signaling on diabetes- induced CD8 T cell activation and hypertension using both global and CD8 T cell-specific P2X7 knockout mice; 2) to investigate the role of insulin-InsR-Panx1 signaling in chronic T cell activation during the progression of diabetes and its contribution to hypertension, employing T cell-specific Panx1 knockout and insulin receptor knockout mice; and 3) to understand the formation of kidney-resident CD8 T cells in type 2 diabetes and their involvement in hypertension, utilizing T cell-specific TGFβ receptor knockout mice. Through this multidisciplinary approach encompassing immunology, metabolism, and cardiovascular physiology, our study aims to uncover the mechanisms driving the continuum between diabetes and hypertension. By elucidating these immune- metabolic pathways, we hope to identify new therapeutic targets to decouple diabetes and hypertension, thus mitigating the burden of metabolic syndrome and its complications.