title: Nucleoside diphosphate kinase B deficiency causes a diabetes-like vascular pathology via up-regulation of endothelial angiopoietin-2 in the retina.
abstract: OBJECTIVE
  Nucleoside diphosphate kinase B (NDPKB) is capable of maintaining the cellular nucleotide triphosphate pools. It might therefore supply UTP for the formation of UDP-GlcNAc from glucose. As NDPKB contributes to vascular dysfunction, we speculate that NDPKB might play a role in microangiopathies, such as diabetic retinopathy (DR). Therefore, we investigated the impact of NDPKB on retinal vascular damage using NDPKB(-/-) mice during development of DR and its possible mechanisms.
  
  
  METHODS
  Pericyte loss and acellular capillary (AC) formation were assessed in streptozotocin-induced diabetic NDPKB(-/-) and wild-type (WT) mice. Expression of angiopoietin-2 (Ang2) and protein N-acetylglucosamine modification (GlcNAcylation) were assessed by western blot and/or immunofluorescence in the diabetic retinas as well as in endothelial cells depleted of NDPKB by siRNA and stimulated with high glucose.
  
  
  RESULTS
  Similar to diabetic WT retinas, non-diabetic NDPKB(-/-) retinas showed a significant decrease in pericyte coverage in comparison with non-diabetic WT retinas. Hyperglycemia further aggravates pericyte loss in diabetic NDPKB(-/-) retinas. AC formation was detected in the diabetic NDPKB(-/-) retinas. Similar to hyperglycemia, NDPKB deficiency induced Ang2 expression and protein GlcNAcylation that were not further altered in the diabetic retinas. In cultured endothelial cells, stimulation with high glucose and NDPKB depletion comparably increased Ang2 expression and protein GlcNAcylation.
  
  
  CONCLUSIONS
  Our data identify NDPKB as a protective factor in the retina, which controls Ang2 expression and the hexosamine pathway. NDPKB-deficient mice are a suitable model for studying mechanisms underlying diabetic retinal vascular damage.
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mybachstr. 14, 68169, Mannheim, Germany.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mybachstr. 14, 68169, Mannheim, Germany.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mybachstr. 14, 68169, Mannheim, Germany.
authors.forename: Vicki-Marie
authors.initials: VM
authors.lastname: Butenschön
authors.affiliation: Division of Experimental Dermatology, Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Bauer
authors.affiliation: Division of Experimental Dermatology, Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Schneider
authors.affiliation: Division of Nephrology, New York University Langone Medical Center, 560 1st Ave, New York, NY, 10016, USA.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
authors.affiliation: 5th Medical Clinic, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mybachstr. 14, 68169, Mannheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mybachstr. 14, 68169, Mannheim, Germany. yuxi.feng@medma.uni-heidelberg.de.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Feng
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006595:Hexosamines / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics* / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D012160:Retina / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D042702:Angiopoietin-2; D006595:Hexosamines; D054778:NM23 Nucleoside Diphosphate Kinases; C517941:Nme2 protein, mouse; D005947:Glucose
keywords: Angiopoietin 2; Diabetic retinopathy; Nucleoside diphosphate kinase B; O-linked acetylglucosamine; Retina