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Demonstration That Polyol Accumulation Is Responsible for Diabetic Cataract by the Use of Transgenic Mice Expressing the Aldose Reductase Gene in the Lens ALAN Y

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Demonstration That Polyol Accumulation Is Responsible for Diabetic Cataract by the Use of Transgenic Mice Expressing the Aldose Reductase Gene in the Lens ALAN Y Proc. Natl. Acad. Sci. USA Vol. 92, pp. 2780-2784, March 1995 Medical Sciences Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens ALAN Y. W. LEE, SOOKJA K. CHUNG, AND STEPHEN S. M. CHUNG* Institute of Molecular Biology, University of Hong Kong, 5 Sassoon Road, Hong Kong Communicated by Y W. Kan, University of California, San Francisco, December 12, 1994 ABSTRACT Aldose reductase (AR) has been implicated cose and galactose, and it has not been demonstrated directly in the etiology of diabetic cataract, as well as in other that AR can reduce these hexoses in vivo. complications. However, the role ofAR in these complications In this report we show that transgenic mice expressing high remains controversial because the strongest supporting evi- levels of AR are susceptible to galactose and diabetic cataracts, dence is drawn from the use of AR inhibitors for which providing the strongest evidence that accumulation of polyols specificity in vivo cannot be ascertained. To settle this issue we is the main factor contributing to sugar cataracts. developed transgenic mice that overexpress AR in their lens epithelial cells and found that they become susceptible to the MATERIALS AND METHODS development of diabetic and galactose cataracts. When the sorbitol dehydrogenase-deficient mutation is also present in Generation of Transgenic Mice. The entire 1.4-kb cDNA these transgenic mice, greater accumulation of sorbitol and from a human AR (hAR) clone with 36-bp 5' and 325-bp 3' further acceleration of diabetic cataract develop. These ge- untranslated regions (16) was released from the Bluescript netic studies demonstrated convincingly that accumulation of vector by Xba I and EcoRV digests and inserted into the Xba polyols from the reduction of hexose by AR leads to the I and Msc I site of the pCAT-Basic vector (Promega) that formation of sugar cataracts. contains the simian virus 40 splice site and poly(A) sequence. The -341 to +49 region of the mouse aA-crystallin promoter Diabetic complications such as neuropathy, nephropathy, ret- (17) was cloned by PCR amplification of BALB/c genomic inopathy, and cataract, etc., occur in both insulin-dependent DNA and inserted into the Xba I and Xma I sites at the 5' end and noninsulin-dependent diabetes mellitus. Hyperglycemia of hAR. A DNA fragment containing the aAcry-hAR hybrid has as the cause of these gene was released from the vector by Tha I and Nde I digestions long been suspected manifestations, and injected into oocytes from CBA egg donors fertilized by and the results of the Diabetic Control and Complications C57BL males. Transgenic mice were identified by PCR screen- Trial (1) appear to confirm it. However, by what mechanism ing of genomic DNA extracted from the tail by using the two elevated blood glucose leads to these complications is unclear. primers as shown (Fig. 1) and then confirmed by Southern blot One theory implicates the polyol pathway as a cause of diabetic hybridization using hAR as a probe (data not shown). cataract because of the discovery of polyols in cataractous Assay ofAR Enzyme Activity. Mouse lens AR crude extract lenses (2) and the identification of aldose reductase (AR) that was prepared, and activity was assayed as described (18). reduces various sugars to their polyols (3, 4). AR reduces Briefly, lenses were isolated from 3-week-old mouse and glucose to sorbitol, which is then converted to fructose by homogenized in a sodium phosphate buffer at 4°C. Crude sorbitol dehydrogenase (SorD). Because sorbitol does not enzyme extract was obtained by spinning down the cell debris, readily diffuse out of cells and its oxidation to fructose is slow, and AR activity was measured spectrophotometrically by the accumulation of sorbitol under the hyperglycemic state monitoring the rate of oxidation of NADPH at 340 nm. would increase the intracellular osmotic pressure, leading to Reaction mix contains 67 mM sodium phosphate (pH 6.2), 5 swelling and eventual rupture of the lens fiber cells (5). The mM DL-glyceraldehyde, 0.4 M lithium sulfate, and 200 ,uM involvement of AR in diabetic cataract is supported by the fact NADPH. An aliquot of enzyme extract was added to initiate that animals such as rats and dogs that have high levels of this the reaction, which was done at 30°C. The unit of AR enzyme enzyme in their lenses are prone to develop diabetic cataract, activity is defined as nmol of NADPH oxidized per min per mg whereas mice that have low lens AR activity are not (6). Rats of protein in the crude extract. and dogs also develop galactose-induced cataracts more Induction of Galactosemia and Diabetes. To induce galac- readily than diabetes-induced cataracts (7). This fact agrees tosemia, both transgenic mice and their normal littermates with the polyol model because galactose is a better substrate were fed with a diet of 50% galactose/50% Purina rat chow at than glucose for AR in vitro, and its reduction product galac- the age of 3 weeks after birth. Hyperglycemia was induced by titol is not further converted to other metabolites, resulting in a single i.p. injection of streptozotocin at a dose of 200 mg/kg faster buildup of this polyol. Additional evidence for the polyol of body weight. Blood glucose was monitored by blood glucose model came from the fact that several AR inhibitors could test strips (HaemoGlukotest, Boehringer Mannheim), and suppress cataract formation in experimentally induced dia- those mice with blood glucose levels >500 mg/dl throughout betic animals (8-10). However, these drugs may inhibit AR by the experimental period were included in this study. Lenses nonspecific hydrophobic interactions (11, 12), and their ben- were examined by dilating the pupils with 1% tropicamide eficial effects may be derived from the inhibition of other (Alcon, Puurs, Belgium), and the progression of cataract was enzymes. The strongest challenge to the polyol model is the divided into three stages as shown in Fig. 2. fact that kinetic analyses (13, 14) and x-ray crystallographic Measurement ofPolyol Level in Mouse Lens. To confirm the studies (15) indicated that AR has a very low affinity for glu- formation of galactitol in galactosemic mouse lens, 3-week-old The publication costs of this article were defrayed in part by page charge Abbreviations: AR, aldose reductase; hAR, human AR; SorD, sorbitol payment. This article must therefore be hereby marked "advertisement" in dehydrogenase. accordance with 18 U.S.C. §1734 solely to indicate this fact. *To whom reprint requests should be addressed. 2780 Downloaded by guest on September 27, 2021 Medical Sciences: Lee et aL Proc. Natl. Acad. Sci. USA 92 (1995) 2781 transgenic mice from line CAR222 and their normal litter- Table 1. Lens AR enzyme level and rate of galactose mates were divided into two groups: (i) normal diet, in which cataract development mice were fed on normal Purina rat chow; (ii) galactose- Time to reach stages of feeding, in which mice were put on a diet of 50% galactose/ 50% Purina rat chow. Four mice from each group were Lens AR galactosemic cataract sacrificed for polyol quantitation beginning 1 week after the enzyme level, (after 50% galactose diet), diet and continuing for 3 consecutive weeks. Their lenses were Transgenic nmol/min per days homogenized, and polyols were extracted by ethanol precipi- mouse line no. mg Stage I Stage II Stage III tation, derivatized by phenylisocyanate, and separated by CAR222 37.9 ± 3.57 2 14 21 HPLC; their elution was then monitored by UV absorption at CAR223 11.1 ± 1.20 N N N 240 nm (19). Similarly, the lens sorbitol level of diabetic CAR435 48.9 ± 3.75 1 14 21 heterozygous and homozygous transgenic mice was measured CAR440 11.1 ± 0.63 N N N at the three time points. CAR648 133.7 ± 8.50 1 10 14 Crossing ofAR Transgenic Mice with SorD-Deficient Mice. CAR222 + N N N Mice homozygous for human AR transgene (hAR+/+) from ARI* two transgenic lines CAR222 and CAR648 were mated with Normal mouse 1.4 ± 0.09 N N N homozygous SorD-deficient mice (mSD-/-) called C57BL/ Normal rat 37.4 ± 1.30 7 14 21 LiA. The offsprings (F1) of these crosses were then mated with Enzyme activities of AR in lenses of five transgenic mouse lines each other, and their progenies (F2) were induced to become were assayed at 3 weeks after birth, and values are expressed as mean diabetic and monitored for cataract development and sorbitol ± SD from four mice. To induce galactose cataract, 3-week-old mice accumulation. The genotypes of the F2 mice were determined were fed with a 50% galactose diet, and the rate of cataract develop- as follows: hAR genotypes were determined by Southern blot ment is represented by the number of days that elapsed before the first hybridization using hAR cDNA as a probe. The hybridized appearance of the three stages of cataract, as defined in Fig. 2. Results hAR band in hAR+/+ mice is twice as intense as hAR+/- mice from normal mice and rats are also included for comparison. To inhibit AR enzyme activity, AR inhibitor (AL01576, 0.5 mg/kg per day) was and absent in hAR-/- mice. mSD genotypes were determined administered daily into the stomach of three mice from line CAR222 by enzyme assay. At the end of the experiment, mice were through a gastric tube throughout the experiment. N, no observable sacrificed, and SorD activity in the liver was measured spec- cataract. trophotometrically by monitoring the oxidation of NADH at *AR inhibitor. 340 nm, as described (20).
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