A decrease in retinal progenitor cells is associated with early features of diabetic retinopathy in a model that combines diabetes and hypertension.
OBJECTIVE
Hyperglycemia and hypertension contribute to the development of diabetic retinopathy, and this may involve alterations in the normal retinal cell cycle. In this work, we examined the influence of diabetes and hypertension on retinal cell replication in vivo and the relationship between these changes and several early markers of diabetic retinopathy.


METHODS
Diabetes was induced with streptozotocin in 4- and 12-week-old spontaneously hypertensive rats (SHR) and their Wistar Kyoto (WKY) controls. The rats were killed 15 days later. Retinal cells stained with bromodeoxyuridine (BrdU) were seen in rats of both ages.


RESULTS
In 12-week-old rats, the number of BrdU-positive retinal cells was higher in SHR than in WKY rats. After 15 days of diabetes mellitus, there was a marked reduction in cell replication only in diabetic SHR (p=0.007). The BrdU-positive cells expressed neural, glial, or vascular progenitor markers. There was greater expression of p27(Kip1) in the ganglion cell layer of both diabetic groups (p=0.05), whereas in the inner nuclear layer there was enhanced expression only in diabetic SHR (p=0.02). There was a marked increase in the retinal expression of fibronectin (p=0.04) and vascular endothelial growth factor (p=0.02) in diabetic SHR that was accompanied by blood-retinal barrier breakdown (p=0.01).


CONCLUSIONS
Concomitant diabetes and hypertension attenuated the proliferation of retinal cells, and it is associated with an increase in p27(Kip1) expression, fibronectin accumulation, and blood-retinal barrier breakdown. The replicative retinal cells displayed characteristics of progenitor cells.
Lopes de Faria
Jacqueline Mendonça
JM
Department of Internal Medicine, Faculty of Medical Sciences, Renal Pathophysiology Laboratory, Investigation in Diabetes Complications, State University of Campinas, Campinas, São Paulo, Brazil. jmlfaria@fcm.unicamp.br
Silva
Kamila Cristina
KC
Boer
Patrícia Aline
PA
Cavalcanti
Tiago Correa
TC
Rosales
Mariana Aparecida Brunini
MA
Ferrari
Ana Luiza
AL
Lopes de Faria
José Butori
JB
D000375:Aging / Q000473:pathology; D000818:Animals; D001813:Blood-Retinal Barrier / Q000503:physiopathology; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002199:Capillary Permeability / Q000502:physiology; D002452:Cell Count; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012160:Retina / Q000473:pathology*; D013234:Stem Cells / Q000473:pathology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D042461:Vascular Endothelial Growth Factor A; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001973:Bromodeoxyuridine