Aldose Reductase-Deficient Mice Develop Nephrogenic Diabetes Insipidus

Abstract

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...

Porcine sperm capacitation involves tyrosine phosphorylation and activation of aldose reductase

“…However, under the present experimental conditions, the SORD inhibitor, CP-470,711, did not show any significant effects on the induction of hyperactivated motility. Although our results suggest that aldose reductase is involved in capacitation not by supplying energy sources but by producing low levels of ROS, both enzymes in the polyol pathway might not be indispensable for sperm to fertilize oocytes, because it has been reported that neither aldose reductase-nor SORD-deficient mice demonstrate any apparent reproductive abnormality (Holmes et al 1982, Ho et al 2000. These results suggest that other pathways compensate the deletion of aldose reductase by regulating physiological ROS levels of sperm in mice.…”

Deletion of Aldose Reductase Leads to Protection against Cerebral Ischemic Injury

“…Age-matched nontransgenic littermates were used as controls in all experiments. Aldose reductase knockout (AR À/À ) mice generated in our laboratory (Ho et al, 2000) were back-crossed to the C57BL/6N strain to the 11th generation (N11), which are considered to be congenic with C57BL/6N mice. Age-matched normal C57BL/6N mice were therefore used as control wild-type mice (AR + / + ).…”

“…To elucidate the role of the polyol pathway enzymes, AR and SD, in cerebral ischemia and related oxidative stress, we challenged AR-and SD-mutant mice (Ho et al, 2000;Ng et al, 1998) with ischemia/reperfusion injury. The findings that various agents can decrease cerebral infarct size after 2 h of middle cerebral artery occlusion (MCAO) with 22-h reperfusion (Ellsworth et al, 2003;Endres et al, 1998a) suggest that such ischemia-induced brain injury can still be reversed.…”

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…The enzyme has also been shown to be an obligatory mediator of ischemic preconditioning (Shinmura et al, 2002). Genetic deletion of Akr1b3 in mice leads to the development of nephrogenic diabetes insipidus (Ho et al, 2000), indicating a potentially critical role of the enzyme in concentrating urine.…”

“…This explains why to-date only four knockout models of the AKRs have been described. Aldose reductase knockout mouse exhibits diabetes insipidus (Ho et al, 2000), whereas Kvβ1 knockout mice have learning and memory impairments (Giese et al, 1998;Need et al, 2003) and alterations in cardiac currents I(to) and I(K slow ) (Aimond et al, 2005). The Kvβ2 knockout has reduced life span, seizures, and exaggerated cold swim induced tremors (Connor et al, 2005;McCormack et al, 2002).…”