Targeting epithelial senescence to augment renal repair

Abstract

Effective renal repair following injury is essential for maintaining normal kidney function and is vital to the health of millions of patients every year. Maladaptive repair occurs when kidneys fail to return to normal levels of function following an injury and have excessive fibrosis and resulting organ impairment. Senescent cells accumulate in multiple organs with increasing age and with disease and are implicated in numerous disease processes, however the mechanism underlying this remains incompletely understood. The elderly and those with chronic kidney disease are most susceptible to disordered repair post injury while also demonstrating the highest burden of senescent cells, suggesting senescent cells may negatively impact renal repair. There is an unmet need for anti-senescent therapies, and new anti-fibrotic therapies to augment post injury repair. Here I demonstrate the persistence of senescent cells in human kidneys during renal repair and show that depletion of senescent cells with a senolytic drug attenuates renal fibrosis in a murine model of reversible ureteric obstruction. I perform the first characterisation in vivo of the post injury renal epithelial senescent transcriptome at a single-cell resolution, identifying multiple novel therapeutic targets in silico and confirm these targets are upregulated in senescent cells in vitro. Inhibition of two of these targets, Protein Disulfide Isomerase Family A Member 3 and Neuropilin-1 attenuate post injury fibrosis in vivo.