Aldose reductase inhibitors kidney

Another complication of diabetes is blindness, which is due to blood vessel damage at the back of the eye (proliferative retinopathy), this accounts for about 12% of all blindness. In hyperglycemia, fructose is only slowly metabolized, and sorbitol accumulates in tissues. Because aldose reductase is found in kidneys, optic nerve, and peripheral neurons, retinopathy and painful neuropathies develop in poorly controlled or long-standing diabetes as a result of sugar alcohol (sorbitol) accumulation. Aldose reductase inhibitors, such as tokestat (5.129) or sorbinil (5.130), have been evaluated as agents to ameliorate these additional symptoms of diabetes. 

A wide range of toxins has now been investigated including the kidney cortical toxins mercury chloride, - p-aminophenol, " ifosfamide, the kidney medullary toxins propyleneimine and 2-bromoethanamine hydrochloride and the liver toxins hydrazine, allyl alcohol, thioacetamide and carbon tetrachloride. The testicular toxin cadmium chloride has also been investigated in detail. The aldose reductase inhibitor HOE-843 has also been studied. ... 

In vivo studies on the polyol pathway suggest a link to ascorbic acid levels. For instance, certain aldose reductase inhibitors and dietary my -inositol appear to correct plasma ascorbic acid levels in rat models of diabetes mellitus. However, the effect was ascribed to changes in kidney function (urinary excretion), and such studies are complicated by the ability of rats to synthesize ascorbic acid (Yue et aL, 1989). 

Takahashi K, Mizukami H, KamataK, Inaba W, KatoN, Hibi C, Yagihashi S (2012) Amelioration of acute kidney injury in lipopolysaccharide-induced systemic inflammatory response syndrome by an aldose reductase inhibitor, fidarestat. PLoS One 7(l) e30134... 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Tissue Location and Role of Aldose Reductase in Animal Models of Diabetic Complications. Aldose reductase (AR) has been located immunohistochemically in many tissues of the dog and rat, most notably, in corneal epithelium, retina, optic nerve, kidney papillae, aortic endothelium and smooth muscle cells as well as peripheral nerve and lens. AR has also been measured in human and monkey retinal mural cells. These cells are thought to provide the structural support for retinal capillaries and their loss is the first abnormality seen in clinical diabetic retinopathy. In addition, AR-like activity has been reported in a human retinoblastoma cell line and sorbinil inhibits this activity in these cells. Finally, a recent report has demonstrated that AR is present in isolated capillaries from bovine retina and cerebral cortex. Therefore, AR appears to be present in all tissues which are uniquely susceptible to deterioration during prolonged exposure to the hyperglycemia of diabetes. Accumulation of the products of the polyol pathway, sorbitol and fructose, has been demonstrated in these tissues and, where tested, sorbinil and other AR inhibitors have been shown to inhibit this accumulation. 

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