Dissecting renal metabolic reprogramming heterogeneity to target kidney fibrosis

ongoing

Chronic kidney disease (CKD) affects 10% of the population and fibrosis driven by excessive accumulation of extracellular matrix (ECM) is the hallmark of CKD. Myofibroblasts are the key ECM producing cells and are activated by cross-talk with injured proximal tubule anChronic kidney disease (CKD) affects 10% of the population and fibrosis driven by excessive accumulation of extracellular matrix (ECM) is the hallmark of CKD. Myofibroblasts are the key ECM producing cells and are activated by cross-talk with injured proximal tubule and immune cells. Although a derangement in fatty acid oxidation (FAO) of tubular epithelium is crucial in the pathophysiology of CKD, the metabolic rewiring of kidney myofibroblasts remains elusive. Our preliminary observations suggest that cell type-specific metabolic shifts could define new cellular subpopulations with a differential role in the fibrogenic response. To understand this, the following objectives have been defined: 1. To decipher the role of FAO in myofibroblasts during kidney fibrosis; 2.To dissect metabolic changes as important drivers of kidney fibrosis and CKD; 3. To validate key metabolic pathways in complex ex vivo models of kidney fibrosis. To address these aims, I will map the genetic and metabolic spatio-temporal features of kidney fibrosis by a combination of cutting-edge multi-omics technologies at large scale (Spatial single cell ATAC sequencing for transcriptomics and Space M for metabolomics). This will be complemented by advanced computational analyses and modeling, using CKD human biopsies and mouse renal samples from available genetic models for myofibroblast tracing and FAO enhancement. Innovative in vitro systems (cell coculture and kidney organoid systems) will be used to identify and target cell type-specific metabolic reprogramming. Strategies based on the modulation of these metabolic shifts will provide a firm basis for novel, metabolism-oriented therapeutic approaches against renal fibrosis and CKD.