Hyperglycaemic memory affects the neurovascular unit of the retina in a diabetic mouse model.
The aim of this study was to evaluate damage to the neurovascular unit in a mouse model of hyperglycaemic memory.



A streptozotocin-induced mouse model of diabetes (C57BL/6J background) received insulin-releasing pellets and pancreatic islet-cell transplantation. Damage to the neurovascular unit was studied by quantitative retinal morphometry for microvascular changes and microarray analysis, with subsequent functional annotation clustering, for changes of the retinal genome.



Sustained microvascular damage was confirmed by persistent loss of pericytes in the retinal vasculature (PC/mm2): compared with healthy controls (1981 ± 404 PC/mm2), the pericyte coverage of the retinal vasculature was significantly reduced in diabetic mice (1571 ± 383 PC/mm2, p < 0.001) and transplanted mice (1606 ± 268 PC/mm2, p < 0.001). Genes meeting the criteria for hyperglycaemic memory were attributed to the cytoskeletal and nuclear cell compartments of the neurovascular unit. The most prominent regulated genes in the cytoskeletal compartment were Ddx51, Fgd4, Pdlim7, Utp23, Cep57, Csrp3, Eml5, Fhl3, Map1a, Mapk1ip1, Mnda, Neil2, Parp2, Myl12b, Dynll1, Stag3 and Sntg2, and in the nuclear compartment were Ddx51, Utp23, Mnda, Kmt2e, Nr6a1, Parp2, Cdk8, Srsf1 and Zfp326.



We demonstrated that changes in gene expression and microvascular damage persist after euglycaemic re-entry, indicating memory.



The datasets generated during and/or analysed during the current study are available in the GEO repository, GSE87433, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=idmbysgctluxviv&acc=GSE87433 .
Fifth Medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
Patrick
P
Friedrichs
Fifth Medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. Andrea.Schlotterer@medma.uni-heidelberg.de.
Andrea
A
Schlotterer
Center of Medical Research, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Carsten
C
Sticht
Fifth Medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
Matthias
M
Kolibabka
Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
Paulus
P
Wohlfart
Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
Axel
A
Dietrich
Clinical Research Unit, Centre of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany.
Thomas
T
Linn
Departmentof Pathology and Medical Biology, Medical Biology section, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Grietje
G
Molema
Fifth Medical Department, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
Hans-Peter
HP
Hammes
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002467:Cell Nucleus / Q000378:metabolism; D019295:Computational Biology; D003599:Cytoskeleton / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000503:physiopathology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D020286:Pericytes / Q000166:cytology / Q000473:pathology; D012160:Retina / Q000473:pathology / Q000503:physiopathology*; D012171:Retinal Vessels / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin
Animal; Microarray; Microvascular disease; Mouse; Retinopathy