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

Vanessa R Williams; Ana Konvalinka; Xuewen Song; Xiaohua Zhou; Rohan John; York Pei; James W Scholey

doi:10.1016/j.kint.2020.01.029

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

Kidney Int. 2020 Jul;98(1):116-132. doi: 10.1016/j.kint.2020.01.029. Epub 2020 Feb 19.

Authors

Vanessa R Williams¹, Ana Konvalinka², Xuewen Song³, Xiaohua Zhou⁴, Rohan John⁵, York Pei⁶, James W Scholey⁷

Affiliations

¹ Institute of Medical Science, University of Toronto, Toronto, Canada. Electronic address: vanessa.williams@mail.utoronto.ca.
² Institute of Medical Science, University of Toronto, Toronto, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Division of Nephrology, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
³ Division of Nephrology, University Health Network, Toronto, Canada.
⁴ Institute of Medical Science, University of Toronto, Toronto, Canada.
⁵ Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Department of Pathology, University Health Network, Toronto, Canada.
⁶ Institute of Medical Science, University of Toronto, Toronto, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Division of Nephrology, University Health Network, Toronto, Canada.
⁷ Institute of Medical Science, University of Toronto, Toronto, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Division of Nephrology, University Health Network, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.

PMID: 32418621
DOI: 10.1016/j.kint.2020.01.029

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.

Keywords: MAPK; chronic kidney disease; drug repurposing; interstitial fibrosis; lysine deacetylase; renal proximal tubule cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Progression
Fibrosis
Glomerulosclerosis, Focal Segmental* / pathology
Humans
Kidney / pathology
Lysine
Mice
Renal Insufficiency, Chronic* / drug therapy
Renal Insufficiency, Chronic* / genetics
Renal Insufficiency, Chronic* / pathology

Substances

Lysine