title: Long-term administration of the histone deacetylase inhibitor vorinostat attenuates renal injury in experimental diabetes through an endothelial nitric oxide synthase-dependent mechanism.
abstract: Epigenetic changes in gene expression play a role in the development of diabetic complications, including nephropathy. Histone deacetylases (HDACs) are a group of enzymes that exert epigenetic effects by altering the acetylation status of histone and nonhistone proteins. In the current study, we investigated the action of the clinically available HDAC inhibitor vorinostat in a mouse model of diabetic nephropathy, with the following aims: to define its effect on the progression of renal injury and to explore its mechanism of action by focusing on its role in regulating the expression of endothelial nitric oxide synthase (eNOS). Control and streptozotocin-diabetic wild-type and eNOS(-/-) mice were treated with vorinostat by daily oral dosing for 18 weeks. Without affecting either blood glucose concentration or blood pressure, vorinostat decreased albuminuria, mesangial collagen IV deposition, and oxidative-nitrosative stress in streptozotocin-wild-type mice. These attenuating effects were associated with a >50% reduction in eNOS expression in mouse kidneys and in cultured human umbilical vein endothelial cells. Vorinostat treatment had no effect on albuminuria, glomerular collagen IV concentration, or mesangiolysis in diabetic mice genetically deficient in eNOS. These observations illustrate the therapeutic efficacy of long-term HDAC inhibition in diabetic nephropathy and emphasize the importance of the interplay between eNOS activity and oxidative stress in mediating these effects.
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada. advania@smh.ca
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.forename: Qingling
authors.initials: Q
authors.lastname: Huang
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Advani
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: White
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Darren A
authors.initials: DA
authors.lastname: Yuen
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.forename: Philip A
authors.initials: PA
authors.lastname: Marsden
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D052250:Nitric Oxide Synthase Type III