title: Renoprotective effect of combined inhibition of angiotensin-converting enzyme and histone deacetylase.
abstract: The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice). We predicted that the combination of an angiotensin-converting enzyme (ACE) inhibitor and a histone deacetylase inhibitor would maximally reverse the disease-associated expression of genes in the kidneys of these mice. Testing the combination of these inhibitors in Tg26 mice revealed an additive renoprotective effect, as suggested by reduction of proteinuria, improvement of renal function, and attenuation of kidney injury. Furthermore, we observed the predicted treatment-associated changes in the expression of selected genes and pathway components. In summary, these data suggest that the combination of an ACE inhibitor and a histone deacetylase inhibitor could have therapeutic potential for various kidney diseases. In addition, this study provides proof-of-concept that drug-induced expression signatures have potential use in predicting the effects of combination drug therapy.
authors.affiliation: Department of Medicine, Division of Nephrology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1243, New York, NY 10029, USA.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhong
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Chen
authors.forename: Ruijie
authors.initials: R
authors.lastname: Liu
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Chuang
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Mallipattu
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tan
authors.forename: Neil R
authors.initials: NR
authors.lastname: Clark
authors.forename: Yueyi
authors.initials: Y
authors.lastname: Deng
authors.forename: Paul E
authors.initials: PE
authors.lastname: Klotman
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000188:drug therapy; D008297:Male; D051379:Mice; D000077337:Vorinostat
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; C044946:benazepril
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