Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome

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Summary HF affects 6.5 million Americans, with almost 1 million new cases per year and costing over $30 billion in healthcare resources. Renal dysfunction (RD) is common in HF, with a reported prevalence over 50%, and is a major risk factor for death. Ultimately, cardiac dysfunction promotes renal fibrotic remodeling and progressive HF-induced RD, a pathophysiologic condition known as cardiorenal syndrome (CRS). Importantly, RD in HF is a potent marker of decreased survival, outperforming traditional metrics of HF disease severity like ejection fraction and functional class, however fundamental research into the mechanisms behind this process are limited. A number of factors preceding fibrosis contribute to the development of CRS, including changes in hemodynamics, neurohormones, cytokines and sympathetic nervous system (SNS) activation. Responsive to each of these changes are leukocytes, including neutrophils, monocytes, macrophages and lymphocytes, some of which have been implicated in CRS. However, few reports have investigated whether they play a reactionary or causative role in the development of CRS-induced renal dysfunction and remodeling in response to HF or how to mitigate their impact in this process. We hypothesize that leukocytes play a fundamental role in regulating CRS, and since RD remains a strong independent predictor for poor prognosis in HF patients, understanding the role of leukocytes and the molecular changes they undergo during CRS progression may offer new strategies by which to alleviate patient mortality. Therefore, we will determine the temporal- and subtype-specific leukocyte infiltration profiles in relation to changes in cardiac and renal structure and function during CRS progression, the impact of their deletion at specific timepoints, as well as perform a dynamic single cell transcriptome analysis of renal cells during CRS and transcriptome analyses of peripheral blood leukocytes from mice and humans with clinically-manifested CRS. In addition, our lab recently showed that modulation of leukocyte-specific β2-adrenergic receptor (β2AR) expression or signaling alters leukocyte targeting and responsiveness to injury in a GPCR kinase (GRK)/β-arrestin (βarr)-dependent manner. Thus, we will define the impact of leukocyte-specific β2AR-dependent signaling on CRS progression and determine how genetic deletion, pharmacologic inhibition or GRK/βarr-biased modulation of leukocyte β2AR signaling impacts CRS development and progression. Completion of this project will generate new molecular and physiologic insight toward the detection and treatment of HF-induced CRS via targeting of leukocyte-dependent processes and responsiveness.