The role of senescence in kidney ageing, injury and fibrosis.

Abstract

Despite treatment advances, chronic kidney disease (CKD) remains an incurable, progressive disease affecting ~850 million people worldwide. Kidney ageing and CKD have many common features, including capillary and epithelial cell loss, increased fibroblast numbers, interstitial fibrosis and chronic immune infiltrates. Consequently, identifying pathways driving the fibrosis and loss of homeostasis shared in both states is a major research priority. Cellular senescence, a cell state characterized by generally irreversible growth arrest with an altered secretory phenotype, is highly conserved across all multicellular organisms. 'Acute' senescence induction with prompt physiological clearance is important for development, contributes to adaptive repair in response to organ injury, and represents a defence against neoplasia. However, the increased numbers of senescent epithelial cells associated with human kidney ageing and CKD include 'chronic' senescent cells, which have been implicated as drivers of kidney dysfunction and fibrosis. Experimental evidence links chronic senescence to kidney leukocyte recruitment and myofibroblast activation. Moreover, pre-clinical studies of senescent cell depletion show extended healthy lifespan, preserved function and reduced fibrosis in multiple organs, including the kidney. Here, we examine current evidence of senescence as a driver of kidney disease and its potential as a therapeutic target.