Aldose reductase (ALR2) is thought to be involved in the pathogenesis of various diseases associated with diabetes mellitus, such as cataract, retinopathy, neuropathy, and nephropathy. However, its physiological functions are not well understood. We developed mice deficient in this enzyme and found that they had no apparent developmental or reproductive abnormality except that they drank and urinated significantly more than their wild-type littermates. These ALR2-deficient mice exhibited a partially defective urine-concentrating ability, having a phenotype resembling that of nephrogenic diabetes insipidus.Aldose reductase (ALR2) is the first enzyme in the polyol pathway. It was first described by Hers in 1956 (13). Using NADPH as a cofactor, it reduces glucose to sorbitol in addition to reducing other sugars to their respective polyols. The activation of the sorbitol pathway under hyperglycemic conditions is thought to be the cause of diabetic lesions in tissues where the import of glucose is independent of insulin, such as the lens, vascular cells, and nervous tissues (18,28). Although ALR2 has been thoroughly studied for its role in the etiology of diabetic complications, its physiological functions are not well understood. ALR2 is present in most tissues surveyed and has been implicated in a wide variety of physiological functions. It is thought to be responsible for synthesizing fructose in the seminal vesicle to be used as the main energy source for sperm motility, because fructose is converted from sorbitol by the enzyme sorbitol dehydrogenase (SORD) (13). ALR2 can efficiently reduce methyglyoxal (35), 4-hydroxynonenal (34), and 3-deoxyglucosone (29), suggesting that it may be responsible for detoxification of these and other harmful metabolites. Another postulated function of ALR2 is osmoprotection in the kidney (1). This is based on the facts that sorbitol is an inert compound ideally suited as an osmolyte and that its intracellular concentration in certain tissues can reach a high enough level to affect osmotic pressure. Further, elevated extracellular NaCl was shown to elicit a marked increase in ALR2 expression and the accumulation of intracellular sorbitol in the cell line cultured from rabbit renal medullae (1), suggesting that kidney cells respond to an increase in extracellular osmotic pressure by producing more sorbitol. In support of this notion, osmotic response elements have been identified in the promoter regions of the rabbit (10) and human (20) ALR2 genes.To test these proposed functions of ALR2, we developed two mouse lines deficient in this enzyme. ALR2 knockout mice (Aldor1 Ϫ/Ϫ ) appeared to grow normally and did not show any obvious abnormalities in their reproductive function. Upon closer examination, they were found to have developed polyuria and polydipsia. These Aldor1 Ϫ/Ϫ mice exhibit a partially defective urine-concentrating ability, leading to a phenotype resembling that of diabetes insipidus (DI).There are several known causes of DI. Deficiency in the synthesis or secretion of t...

Aldose reductase (AR), best known as the first enzyme in the polyol pathway of sugar metabolism, has been implicated in a wide variety of physiological functions and in the etiology of diabetic complications. We have determined the structures and chromosomal locations of the mouse AR gene (Aldor1) and of two genes highly homologous to Aldor1: the fibroblast growth factor regulated protein gene (Fgfrp) and the androgen regulated vas deferens protein gene (Avdp). The number of introns and their locations in the mouse Aldor1 gene are identical to those of rat and human AR genes and also to those of Fgfrp and Avdp. Mouse Aldor1 gene was found to be located near the Cald1 (Caldesmon) and Ptn (Pleiotropin) loci at the proximal end of chromosome 6. The closely related genes Fgfrp and Avdp were also mapped in this region of the chromosome, suggesting that these three genes may have arisen by a gene duplication event.