Connectivity mapping of a chronic kidney disease progression signature identified lysine deacetylases as novel therapeutic targets.

Abstract

Tubulointerstitial injury is an important determinant of chronic kidney disease progression, yet treatment is limited. Accordingly, we derived a chronic kidney disease progression signature based on aging and disease in Col4a3^-^/^- mice, a model associated with proteinuria and progressive loss of kidney function. Computational drug repurposing with the Connectivity Map identified vorinostat, a lysine deacetylase inhibitor, as a candidate treatment to reverse progression signature gene expression. Vorinostat administration significantly increased the lifespan of Col4a3^-^/^- mice and attenuated tubulointerstitial fibrosis and JNK phosphorylation in the kidneys of Col4a3^-^/^- mice. In vitro, vorinostat reduced albumin- and angiotensin II-induced activation of canonical mitogen-activated protein kinases in kidney tubular epithelial cells. Finally, a subset of murine progression signature genes was differentially expressed across kidney transcriptomic data from patients with focal segmental glomerulosclerosis, IgA nephropathy, and diabetic nephropathy. Thus, our findings suggest that lysine deacetylase inhibition may be a novel treatment to chronic kidney disease associated with proteinuria and progressive tubulointerstitial injury.