Aldose reductase inhibitor fidarestat attenuates leukocyte-endothelial interactions in experimental diabetic rat retina in vivo.
OBJECTIVE
Dysregulation of the polyol pathway has been implicated as a major cause of diabetic retinopathy. The aldose reductase inhibitor fidarestat was recently reported to prevent retinal oxidative stress and overexpression of vascular endothelial growth factor (VEGF) protein in diabetic rats. In this study, we investigated the effect of fidarestat on leukocyte-endothelial cell interactions in an in vivo experimental model for diabetic retina.


METHODS
Diabetes was induced in six-week-old male Long-Evans rats by intraperitoneal injection of streptozotocin (STZ) (75 mg/kg). The rats were divided into four experimental groups: non-diabetic control rats, untreated diabetic rats, and diabetic rats treated with a low (4 mg/kg/day) or high (16 mg/kg/day) oral dose of fidarestat. After four weeks of treatment, accumulated leukocytes in the retina were counted in vivo by acridine orange digital fluorography. Intercellular adhesion molecule-1 (ICAM-1) and VEGF-164 mRNA levels in the retina were analyzed using the quantitative reverse transcription-polymerase chain reaction. ICAM-1 protein expression in the retina was investigated by immunohistochemistry.


RESULTS
Fidarestat treatment significantly decreased concentrations of sorbitol and fructose in the retinas of STZ-induced diabetic rats. Leukocyte accumulation in the retinas of fidarestat-treated rats was significantly less than in the untreated diabetic group (P < 0.01). Fidarestat treatment significantly reduced the expression ICAM-1 mRNA, but not VEGF-164 mRNA, in the retina of diabetic rats. Immunohistochemical study also revealed the suppressive effect of fidarestat on expression of ICAM-1.


CONCLUSIONS
Oral administration of fidarestat attenuated leukocyte accumulation in the retina of STZ induced-diabetic rats, suggesting that fidarestat may have a therapeutic role in preventing the progression of diabetic retinopathy.
Hattori
Tomoaki
T
Department of Ophthalmology and Visual Sciences, Nagoya City University Graduate School of Medicine, 1 Kawasumi, Nagoya, Japan.
Matsubara
Akihisa
A
Taniguchi
Kaori
K
Ogura
Yuichiro
Y
D000165:Acridine Orange; D000284:Administration, Oral; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000517:prevention & control; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes; D015590:Fluorophotometry; D005632:Fructose / Q000378:metabolism; D048289:Imidazolidines / Q000008:administration & dosage*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013012:Sorbitol / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D001786:Blood Glucose; D005456:Fluorescent Dyes; D048289:Imidazolidines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D018799:Intercellular Adhesion Molecule-1; D005632:Fructose; D013012:Sorbitol; C077139:fidarestat; D000449:Aldehyde Reductase; D000165:Acridine Orange