Metabolic deregulation, genome instability, and the progression of chronic kidney disease

点击翻译按钮获取中文摘要

Chronic kidney disease (CKD) is a global health burden that affects 10-15% of the population. Moreover, CKD has been identified as a major risk factor for cardiovascular mortality. CKD can result from various different renal disorders and is characterized by loss of functional renal tubules, loss of renal microvasculature, and progressive fibrosis. Recent clinical, genetic and experimental evidence suggested genome instability in renal tubular epithelial cells as a critical pathogenic factor in renal fibrosis and CKD progression. Notably, accumulation of DNA damage has also been observed in extra-renal cells in CKD, indicating systemic effects of CKD on genome stability. We hypothesize that the accumulation of unresolved DNA damage and the resulting transcriptomic, epigenetic and metabolic changes form a vicious circle and represent the main driving forces of renal fibrosis and CKD progression. Therefore, the overarching aim of this project is to analyze the interplay of genome instability and transcriptional and metabolic deregulation in the pathogenesis of CKD. Based on well-established mouse models we aim to gain mechanistic insights into genome instability as a driver of kidney disease. To this end, we will characterize metabolic, transcriptomic, and epigenetic alterations caused by DNA damage in the kidney and analyze the effects of dietary interventions on disease progression. Specifically, we will (1) analyze how defects in DNA repair may affect genomic stability causing renal fibrosis and end-stage-renal failure, (2) address signaling networks involved in genome maintenance in the kidney, and (3) study the interplay between altered metabolism and renal function loss and genomic instability in disease progression. Ultimately, we aim to develop strategies for future clinical applications targeting renal genome instability and preventing CKD.