Uveitis, an ocular inflammatory disease of unknown etiology, is a major complication during autoimmune disorders and infections and is associated with severe visual impairment. Uveitis may result from direct involvement of the uveal tract or indirect inflammation of adjacent eye tissues. Inflammation is an example of cytotoxicity caused by the formation of reactive oxygen species (ROS)-sensitive NF-KB dependent inflammatory cytokines and chemokines, and their autocrine and paracrine effects. However, the mechanisms through which increased ROS and inflammatory markers cause ocular inflammation are not well understood. Our recent studies have shown that aldose reductase (AR), which catalyzes the reduction of lipid peroxidation-generated lipid derived aldehydes (LDAs) and their glutathione conjugates, is an obligatory mediator of cytokine, chemokine, growth factor -induced activation of NF-KB and AP1 via PLC/PKC/IKKIMAPK in various cell lines including human lens epithelial cells (HLECs) and macrophages. We have also shown that AR inhibition prevents bacterial endotoxin (LPS)-induced production of inflammatory markers such as nitric oxide, TNF-a, PGE2 and Cox-2 in HLECs as well as in rat eyes. Our preliminary studies also suggest that AR inhibition prevents endotoxin and autoimmune-induced uveitis in rats. Therefore, our long-term goal is to understand the mechanisms by which AR contributes to ocular inflammation, and to use AR inhibitors to prevent uveitis and its associated complications in non-diabetics and diabetes. We will now systematically test our central hypothesis """"""""that AR's catalytical activity plays a pivotal role in the transduction of ROS -induced inflammatory response leading to uveitis"""""""" by investigating the role of AR in mediating LPS-induced inflammatory response in cultured ocular epithelial cells as well as rodent models of uveitis.
HEALTH Relevance: Uveitis, a potentially sight threatening disease, is of unknown origin and non- specific anti-inflammatory drugs (with concomitant side effects) are often the only choice for the treatment. We will use cell culture and animal models in our investigations to better understand the basic mechanisms of this ocular disease and lay the foundation for bringing new therapeutic approaches to the clinic.
| Kalariya, Nilesh M; Shoeb, Mohammad; Reddy, Aramati B M et al. (2013) Piceatannol suppresses endotoxin-induced ocular inflammation in rats. Int Immunopharmacol 17:439-46 |
| Kalariya, Nilesh M; Ramana, Kota V; Vankuijk, Frederik J G M (2012) Focus on molecules: lutein. Exp Eye Res 102:107-8 |
| Yadav, Umesh C S; Srivastava, Satish K; Ramana, Kota V (2012) Prevention of VEGF-induced growth and tube formation in human retinal endothelial cells by aldose reductase inhibition. J Diabetes Complications 26:369-77 |
| Kalariya, Nilesh M; Shoeb, Mohammad; Ansari, Naseem H et al. (2012) Antidiabetic drug metformin suppresses endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci 53:3431-40 |
| Srivastava, Satish K; Yadav, Umesh C S; Reddy, Aramati B M et al. (2011) Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders. Chem Biol Interact 191:330-8 |
| Reddy, Aramati B M; Tammali, Ravinder; Mishra, Rakesh et al. (2011) Aldose reductase deficiency protects sugar-induced lens opacification in rats. Chem Biol Interact 191:346-50 |
| Yadav, Umesh C S; Shoeb, Mohammad; Srivastava, Satish K et al. (2011) Amelioration of experimental autoimmune uveoretinitis by aldose reductase inhibition in Lewis rats. Invest Ophthalmol Vis Sci 52:8033-41 |
| Kalariya, Nilesh M; Ramana, Kota V; Srivastava, Satish K et al. (2011) Post-translational protein modification by carotenoid cleavage products. Biofactors 37:104-16 |
| Kalariya, Nilesh M; Reddy, Aramati B M; Ansari, Naseem H et al. (2011) Preventive effects of ethyl pyruvate on endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci 52:5144-52 |
| Ramana, Kota V (2011) ALDOSE REDUCTASE: New Insights for an Old Enzyme. Biomol Concepts 2:103-114 |
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