RGD Reference Report - Aldose reductase inhibition prevents endotoxin-induced uveitis in rats. - Rat Genome Database

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Aldose reductase inhibition prevents endotoxin-induced uveitis in rats.

Authors: Yadav, UC  Srivastava, SK  Ramana, KV 
Citation: Yadav UC, etal., Invest Ophthalmol Vis Sci. 2007 Oct;48(10):4634-42.
RGD ID: 8548683
Pubmed: PMID:17898287   (View Abstract at PubMed)
PMCID: PMC2377062   (View Article at PubMed Central)
DOI: DOI:10.1167/iovs.07-0485   (Journal Full-text)

PURPOSE: The purpose of the present study was to elucidate the role of the polyol pathway enzyme aldose reductase (AR) in the mediation of ocular inflammation in a rat model of endotoxin-induced uveitis (EIU). METHODS: EIU was induced by a subcutaneous injection of 200 microg lipopolysaccharide (LPS) in male Lewis rats treated with the AR inhibitor, zopolrestat (25 mg/kg body weight, intraperitoneally) or its carrier. The rats were killed 24 hours after LPS injection, the eyes were enucleated immediately, and aqueous humor (AqH) was collected. The number of infiltrating cells, protein concentration, and levels of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, and prostaglandin E(2) (PGE(2)) in the AqH were determined. Immunohistochemical analysis was performed in paraformaldehyde-fixed eye sections by staining with antibodies against iNOS, COX-2, TNF-alpha, NF-kappaB, and AR. The levels of reactive oxygen species (ROS) in rat eye sections were determined by dihydroethidium (hydroethidine) fluorescence staining. RESULTS: In the EIU rat eye AqH, both the number of infiltrating cells and protein concentrations of the inflammatory markers, TNF-alpha, NO, and PGE(2) were significantly higher than in the control rats, and inhibition of AR by zopolrestat suppressed the LPS-induced increases. The LPS-induced increased expression of AR, TNF-alpha, iNOS, and COX-2 proteins in the ciliary body, corneal epithelium, and retinal wall was also significantly inhibited by zopolrestat. Furthermore, AR inhibition prevented the LPS-induced increased levels of ROS and activation of NF-kappaB in the ciliary body, corneal epithelium, and retinal wall of the rat eye. AR inhibition also prevented the LPS-induced activation of NF-kappaB and expression of COX-2 and iNOS in the human monocyte cell line U-937. CONCLUSIONS: The results indicate that AR inhibition suppresses the inflammation in EIU by blocking the expression and release of inflammatory markers in ocular tissues, along with the attenuation of NF-kappaB activation. This finding suggests that AR inhibition could be a novel therapeutic target for the treatment of uveitis and associated ocular inflammation.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Endotoxin-Induced Uveitis treatmentISOAkr1b1 (Rattus norvegicus)8548683; 8548683 RGD 
Endotoxin-Induced Uveitis treatmentIDA 8548683 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Akr1b1  (aldo-keto reductase family 1 member B1)

Genes (Mus musculus)
Akr1b1  (aldo-keto reductase family 1 member B)

Genes (Homo sapiens)
AKR1B1  (aldo-keto reductase family 1 member B)

Additional Information