Deciphering the genetic, functional, and therapeutic roles of TREM2 in diabetic kidney disease - Project Summary Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide, yet current therapies fail to adequately address critical drivers to its progression: lipid- driven inflammation, immune dysregulation, and fibrosis that drive its progression. Triggering receptor expressed on myeloid cells 2 (TREM2), a receptor specifically expressed on macrophages, has emerged as a pivotal regulator of lipid metabolism and immune responses in metabolic disorders, but its role in DKD remains poorly understood, necessitating further investigation. Our preliminary data suggest that TREM2 exerts a protective role in DKD by mitigating lipid-driven injury and inflammation. Furthermore, we identified the TREM2 R47H mutation, a known risk factor for impaired macrophage function in neurodegenerative diseases-as a susceptibility variant for CKD. Soluble TREM2 (sTREM2), a cleavage product of TREM2, correlates with kidney function decline and inflammatory biomarkers in DKD patients, underscoring its potential as both a prognostic indicator and a therapeutic biomarker. Together, these findings establish TREM2 as a compelling target for elucidating DKD pathogenesis and for the development of innovative biomarkers and therapies. To address these knowledge gaps, we propose three synergistic aims. Aim 1 will dissect the functional and disease-modifying consequences of the TREM2 R47H mutation on macrophage function and DKD progression, leveraging genetic models and lipid-stressed macrophage assays. Next, we will define the molecular mechanisms underlying sTREM2 cleavage, its functional role in macrophage-tubule crosstalk, and its utility as a biomarker for disease progression and therapeutic response (Aim 2). Finally, we will explore the therapeutic potential of TREM2 activation, employing a novel agonist antibody to restore macrophage functionality, reduce lipid-driven injury, and improve kidney outcomes in DKD models (Aim 3). By integrating genetic, mechanistic, and therapeutic strategies, this research aims to unravel the intricate interplay between macrophage lipid metabolism and immune regulation in DKD. Moreover, it seeks to establish a robust framework for TREM2-targeted therapies and sTREM2-based biomarkers, advancing precision medicine approaches to transform the care and prognosis of patients with DKD.
