The transforming growth factor-beta pathway is a common target of drugs that prevent experimental diabetic retinopathy.
OBJECTIVE
Prevention of diabetic retinopathy would benefit from availability of drugs that preempt the effects of hyperglycemia on retinal vessels. We aimed to identify candidate drug targets by investigating the molecular effects of drugs that prevent retinal capillary demise in the diabetic rat.


METHODS
We examined the gene expression profile of retinal vessels isolated from rats with 6 months of streptozotocin-induced diabetes and compared it with that of control rats. We then tested whether the aldose reductase inhibitor sorbinil and aspirin, which have different mechanisms of action, prevented common molecular abnormalities induced by diabetes. The Affymetrix GeneChip Rat Genome 230 2.0 array was complemented by real-time RT-PCR, immunoblotting, and immunohistochemistry.


RESULTS
The retinal vessels of diabetic rats showed differential expression of 20 genes of the transforming growth factor (TGF)-beta pathway, in addition to genes involved in oxidative stress, inflammation, vascular remodeling, and apoptosis. The complete loop of TGF-beta signaling, including Smad2 phosphorylation, was enhanced in the retinal vessels, but not in the neural retina. Sorbinil normalized the expression of 71% of the genes related to oxidative stress and 62% of those related to inflammation. Aspirin had minimal or no effect on these two categories. The two drugs were instead concordant in reducing the upregulation of genes of the TGF-beta pathway (55% for sorbinil and 40% for aspirin) and apoptosis (74 and 42%, respectively).


CONCLUSIONS
Oxidative and inflammatory stress is the distinct signature that the polyol pathway leaves on retinal vessels. TGF-beta and apoptosis are, however, the ultimate targets to prevent the capillary demise in diabetic retinopathy.
Gerhardinger
Chiara
C
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. chiara.gerhardinger@schepens.harvard.edu
Dagher
Zeina
Z
Sebastiani
Paola
P
Park
Yong Seek
YS
Lorenzi
Mara
M
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D048289:Imidazolidines / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D012160:Retina / Q000503:physiopathology; D012171:Retinal Vessels / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D048289:Imidazolidines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D012313:RNA; C026411:sorbinil; D001241:Aspirin