Satish K. Srivastava, Ph.D., Professor
The major focus of my research is to study the role of aldose reductase (AR) in the development of diabetic complications and to develop therapeutic strategies to suppress the complications of diabetes, in particularly, retinopathy, cataractogenesis and cardio-vascular diseases. We have demonstrated that AR besides reducing glucose to sorbitol, efficiently reduces lipid peroxidation- derived aldehydes such as 4-hydroxynonenal (HNE) and their conjugates with glutathione. Our site-directed mutagenesis and structural studies suggest that AR has specific glutathione binding site. We have recently identified that AR regulates the oxidative stress signals induced by cytokines, chemokines and hyperglycemia. Inhibition or ablation of AR prevents the activation of redox-sensitive transcription factors such as NF-kB and AP1 in cultured cells. Using AR inhibitors, we have demonstrated that this enzyme plays an essential role in restenosis of balloon injured carotid artery in normal and diabetic rats. We have also shown that inhibition/ablation of this protein attenuates the proliferation of smooth muscle cells and apoptosis of endothelial and epithelial cells. These results suggest that AR has a significant role in the progression of oxidative stress- induced signals and thereby in the development of diabetic complications. Furthermore, we have demonstrated that AR is involved in ischemia-reperfusion injury, atherosclerosis and heart failure.
Another area of interest in this lab is to investigate the regulation of AR under various physiological and pathological conditions. Investigations are being carried out to understand how AR is modified in the presence of an iNOS substrate (L-arginine) and inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), since treatment with L-NAME enhanced AR activity and sorbitol accumulation in several
tissues of normal and diabetic rats and L-arginine that increases NO-levels significantly inhibited AR activity. These results suggest that under normoglycemic conditions AR activity and sorbitol formation are partially repressed in most tissues by concurrent generation of endogenous NO, and that during hyperglycemia, the regulation of the polyol pathway by NO is elevated. We further identified that AR undergoes S-glutathiolation in the presence of NO-donors. Thus, our observations suggest that restoring NO availability in diabetics should inhibit AR and prevent sorbitol accumulation that may represent a potentially useful strategy for preventing or delaying the development of secondary complications.
We are currently investigating the molecular mechanisms that underlie the involvement of AR in tumorogenesis and inflammation. These areas of research promise to provide additional avenues for developing therapeutic strategies for prevention or therapy of inflammation-related diseases.
We are also investigating the role of a novel aminopeptidase recently identified by us in the lens and liver of rat and bovine. The inhibition of this protease by bestatin prevents hyperglycemia –induced lens opacification in organ cultured rat lens and globalization of rat lens fiber cells. Further work is in progress to identify the structural and kinetic properties of this protease and synthesize structure –based inhibitor(s) for therapeutic use.