Targeting epithelial senescence to augment renal repair
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Date
01/03/2022Author
O’Sullivan, Eoin Daniel
Metadata
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.