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...

Aldose Reductase and Cardiovascular Diseases, Creating Human-Like Diabetic Complications in an Experimental Model

“…In part, this might be because the relatively low AR expression in the mouse has allowed it to develop other defenses. Nerve conduction velocity, which is reduced in diabetic rats by the overexpression of AR, remains completely normal in the AR knockout mouse 82. Similarly, cardiac contractile function appears normal with AR genetic deletion, an observation consistent with the lack of change in heart function with AR pharmacological inhibition 25, 41, 63, 86, 87.…”

“…Despite the fact that AR is absent from all tissues, these genetically-engineered mice have minimal phenotype; they have normal structural, biochemical, reproductive and physiological properties. Consistent with the known osmoregulatory function of AR, their only abnormality is mild polyuria compensated by mild polydipsia 82. Urine and blood divalent cation concentration was also slightly altered, but it remains unclear if the changes were secondary to mild chronic diuresis or if AR plays a role in maintaining systemic divalent cation levels 83.…”

“…Adding to the AR functional conundrum are data from AR “knockout” mice 82. Despite the fact that AR is absent from all tissues, these genetically-engineered mice have minimal phenotype; they have normal structural, biochemical, reproductive and physiological properties.…”

Aldose reductase deficiency protects sugar-induced lens opacification in rats

“…However, these rats were not able to produce littermates, indicating their reproductive abnormalities. In contrast, AKR1B1 null mice showed no apparent growth and reproductive abnormalities [24]. Since we failed to generate littermates, we examined the protective effect of knockdown of AKR1B1 against hyperglycemic cataractogenesis in rat lenses.…”

A spontaneously immortalized Schwann cell line from aldose reductase‐deficient mice as a useful tool for studying polyol pathway and aldehyde metabolism

“…Previous studies have reported that AR‐deficient mice created by genetic manipulation exhibit no obvious phenotypes except for a partially defective urine‐concentrating ability with renal structural abnormalities (Ho et al . ; Yang et al . ).…”