Vitamin K1 prevents diabetic cataract by inhibiting lens aldose reductase 2 (ALR2) activity

Abstract

This study investigated the potential of vitamin K1 as a novel lens aldose reductase inhibitor in a streptozotocin-induced diabetic cataract model. A single, intraperitoneal injection of streptozotocin (STZ) (35 mg/kg) resulted in hyperglycemia, activation of lens aldose reductase 2 (ALR2) and accumulation of sorbitol in eye lens which could have contributed to diabetic cataract formation. However, when diabetic rats were treated with vitamin K1 (5 mg/kg, sc, twice a week) it resulted in lowering of blood glucose and inhibition of lens aldose reductase activity because of which there was a corresponding decrease in lens sorbitol accumulation. These results suggest that vitamin K1 is a potent inhibitor of lens aldose reductase enzyme and we made an attempt to understand the nature of this inhibition using crude lens homogenate as well as recombinant human aldose reductase enzyme. Our results from protein docking and spectrofluorimetric analyses clearly show that vitamin K1 is a potent inhibitor of ALR2 and this inhibition is primarily mediated by the blockage of DL-glyceraldehyde binding to ALR2. At the same time docking also suggests that vitamin K1 overlaps at the NADPH binding site of ALR2, which probably shows that vitamin K1 could possibly bind both these sites in the enzyme. Another deduction that we can derive from the experiments performed with pure protein is that ALR2 has three levels of affinity, first for NADPH, second for vitamin K1 and third for the substrate DL-glyceraldehyde. This was evident based on the dose-dependency experiments performed with both NADPH and DL-glyceraldehyde. Overall, our study shows the potential of vitamin K1 as an ALR2 inhibitor which primarily blocks enzyme activity by inhibiting substrate interaction of the enzyme. Further structural studies are needed to fully comprehend the exact nature of binding and inhibition of ALR2 by vitamin K1 that could open up possibilities of its therapeutic application.

Repression of Polyol Pathway Activity by Hemidesmus indicus var. pubescens R.Br. Linn Root Extract, an Aldose Reductase Inhibitor: An In Silico and Ex Vivo Study

“…PyMol molecular viewer (The PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC) and Discovery Studio Visualizer (Discovery Studio Visualizer ver. 20.1.0.19295) [ 23 ] was used for analyzing the ligand–protein interactions of the compounds.…”

Erworbene Katarakte

“…Infolge der erhöhten Glukosekonzentration im Kammerwasser kommt es zur erhöhten intrazellulären Akkumulation von Sorbitol in der Linse. Dies geschieht über den ersten Schritt im Polyol-Weg mithilfe der Aldose-Reduktase, deren therapeutische Inhibition zunehmend an Bedeutung zu gewinnen scheint 22 . Der aus der intralentalen Sorbitol-Akkumulation resultierende hyperosmotische Effekt trägt maßgeblich zur Kataraktogenese bei, weil Linsenfasern als Folge dessen aufquellen und degenerieren.…”

Diet and Obesity-Induced Methylglyoxal Production and Links to Metabolic Disease

“…Enzymes in the SSAO family form MG during amino acid breakdown and are highly expressed in adipose tissue and in endothelial cells. , Inhibiting SSAO enzymes decreased MG levels, protected pancreatic beta-cells, decreased weight gain and fat deposition, and alleviated the symptoms of diabetic complications. − AR forms MG through the polyol pathway and is associated with the development of many diabetic complications; it was first described for its role in causing lens damage . Its inhibition decreased MG levels and the incidence of diabetic complications. ,− Intriguingly, MG increased the expression and activity of AR . Aldolase B, which produces MG through glycolysis, is highly expressed in mouse and human subjects with T2D and is negatively associated with insulin secretion. − It is also associated with metabolic syndrome. , Aldolase knockdown decreased MG levels and prevented endothelial cell dysfunction .…”