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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2294-2298
Copyright © 1997 by The Endocrine Society

Clinical Studies

Aldose Reductase Gene Expression Is Increased in Diabetic Nephropathy1

V. O. Shah, R. I. Dorin, Y. Sun, M. Braun and P. G. Zager

Department of Internal Medicine, University of New Mexico Health Sciences Center (V.O.S., Y.S., M.B., P.G.Z.) Albuquerque 87131; the Veterans Administration Medical Center (R.I.D.), Albuquerque, New Mexico 87108

Address all correspondence and requests for reprints to: Dr. Philip Zager, Department of Internal Medicine, University of New Mexico Health Sciences Center, Fifth Floor ACC, 2211 Lomas NE, Albuquerque, New Mexico 87131.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Aldose reductase gene expression is increased in insulin-dependent diabetes mellitus (IDDM) with nephropathy. Epidemiology studies in patients with IDDM and noninsulin-dependent diabetes mellitus (NIDDM) are consistent with the hypothesis that a genetic factor(s) influences the risk for kidney disease of diabetes mellitus (KDDM). Aldose reductase (AR), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene product. The present study explored the hypothesis that AR gene expression is increased in peripheral blood mononuclear cells obtained from patients with KDDM. We studied four groups of volunteers: group I, normal subjects; group II, IDDM without nephropathy; group III, IDDM with kidney disease; and group IV, nondiabetics with kidney disease. AR messenger ribonucleic acid was measured by a ribonuclease protection assay. The results are expressed as the mean and 95% confidence interval (CI) of the AR/ß-actin messenger ribonucleic acid molar ratios (AR/ß-actin R). Among diabetics, the AR/ß-actin R was higher in group III (0.088; CI, 0.068–0.108) than in group I (0.045; CI, 0.033–0.057; P < 0.01). There were no significant differences in age, hemoglobin A1c, or duration of diabetes between groups II and III (P = NS). The AR/ß-actin R in group III was also higher than that in group II (0.045; CI, 0.030–0.060; P < 0.01) or group IV (0.019; CI, 0.011–0.027; P < 0.001). In contrast, among nondiabetics, AR/ß-actin R values were 2-fold lower in group IV than in group I (P < 0.01). The results of this study are consistent with the hypothesis that the degree of AR gene expression modulates the risk of KDDM.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
KIDNEY DISEASE of diabetes mellitus (KDDM) is a leading cause of end-stage renal disease (1). The prevalence of KDDM varies widely among different diabetic populations, suggesting that the risk is controled by a genetic factor(s) (2, 3, 4, 5, 6, 7). In patients with insulin-dependent diabetes (IDDM) in Denmark (8), the incidence of persistent proteinuria was low during the first 10 yr and then increased. The peak incidence occurred after 15–17 yr of diabetes. The cumulative incidence of persistent proteinuria was 30–40% after 40 yr. In contrast, in IDDM patients at the Joslin Clinic, the first cases of proteinuria occurred after 5 yr (9) and then declined. The incidence increased rapidly over the next 10 yr, peaked at 25/1000 patient yr, and then declined. The cumulative incidence after 40 yr was 30%. Among NIDDM patients, the prevalence of KDDM varies significantly between ethnic groups, ranging from 2.4% in Hong Kong to 60% in Pima Indians (3, 4, 10). In the U.S., the incidence and prevalence of diabetes-related end-stage renal disease are higher in Hispanics and Native Americans than in non-Hispanic whites in the United States (11). The disparity in the prevalence of KDDM in different populations supports a role for genetic factors in the pathogenesis of KDDM (10).

Considerable interest has focused on the enzyme aldose reductase (AR) as a candidate gene product. AR catalyzes the NADPH-dependent reduction of sugar aldehydes to their corresponding sugar polyols. The polyol pathway is present in lens (12, 13), eye (14), nerve (15), and kidney (14, 16) and has been implicated in the pathogenesis of cataract formation (17, 18), retinopathy (19), neuropathy (20), and nephropathy (21, 22, 23). In contrast, Bondy et al., using in situ hybridization histochemistry, was unable to detect AR messenger ribonucleic acid (mRNA) in renal cortex (24). However, we demonstrated significant quantities of both AR immunoreactive protein (IRP) and AR mRNA in the renal cortex, intact glomeruli, and cultured mesangial cells of rats (25, 26). Other investigators have also demonstrated the polyol pathway in mesangial cells (27). We reported the presence of polyol-dependent regulation of AR gene expression in renal cortex (25). Elevated AR levels occur in neutrophils (28), erythrocytes (29, 30), and mononuclear cells (31) isolated from patients with diabetic complications. Hamada et al. reported that diabetics who developed severe complications in less than 20 yr had the highest red blood cell (RBC) AR activity. In contrast, long standing diabetics, with no complications, had the lowest RBC AR activity (29).

The present study explores the hypothesis that AR gene expression is increased in peripheral blood mononuclear cells (PBMC) obtained from patients with KDDM compared to those from diabetics without KDDM. To test this hypothesis we studied four groups of volunteers: group I, controls (normal subjects); group II, IDDM without nephropathy; group III, IDDM with KDDM; and group IV, nondiabetic kidney disease. Volunteers were classified as having overt kidney disease if they had a serum creatinine level above 1.5 g/dL and/or a urinary protein/creatinine ratio (UPCR) above 0.3.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Human subjects

The protocol was approved by the human subject research review committee of the University of New Mexico Health Sciences Center. Informed written consent was obtained from all volunteers. We studied four groups of volunteers (n = 81): group I, normal subjects without evidence of renal disease (n = 25); group II, IDDM with no evidence of KDDM (n = 19); group III, IDDM with overt KDDM (n = 19); and group IV, nondiabetic with renal disease (n = 18). A complete medical history and physical examination were performed on each volunteer. Three random daytime spot urine samples were obtained from each participant for determination of the UPCR. Serum creatinine and glycosylated hemoglobin (Glyc Hgb) were measured in venous blood obtained from a forearm vein. Subjects were classified into normoglycemic and diabetic categories according to WHO criteria.

Specific ribonuclease (RNase) protection assay for measuring AR-mRNA in PBMC

PBMCs were isolated by Ficoll-Hypaque density gradient centrifugation. Human AR complementary RNA (cRNA) probe was generated from the 3'-untranslated region of human AR by restriction digestion of the pGEM3 plasmid containing human placental AR complementary DNA (cDNA) with Sau3AI. A 222-nucleotide Sau3AI-EcoRI antisense cRNA was transcribed from 1 µg template DNA using the T7 RNA polymerase (Promega, Madison, WI) to a specific activity of 5 to 10 x 109 cpm/µg RNA. A second probe, derived from human ß-actin cDNA, was included in all hybridizations to control for variability in the amount of RNA loaded and the efficiency of hybridization. The human ß-actin probe was prepared by subcloning the KpnI-EcoRI fragment of human ß-actin into the SmaI site of the pTRIPLEscript vector (Ambion, Woodward, TX) in a sense orientation. The ß-actin plasmid was digested with DdeI, and the cRNA probe was transcribed with T7 RNA polymerase to yield a cRNA protecting a 129-nucleotide mRNA fragment of human ß-actin. Probe preparation was performed as described above, except that cold uridine triphosphate (20 µmol/L, final concentration) was included in the reaction to decrease the specific activity to approximately 30-fold. This reduced the differences in signal intensities that might have occurred given the large molar excess of ß-actin relative to AR mRNA in PBMC.

The DNA template was removed by the addition of 1 U RNase-free deoxyribonuclease I (Ambion, Austin, TX), followed by phenol-chloroform extraction. Free nucleotides were removed by spin chromatography with Sephadex G-50, and the probe was ethanol precipitated with 10 µg transfer RNA carrier, resuspended in formamide loading buffer, denatured at 95 C, and isolated by autoradiography on 5% denaturing PAGE containing 7 mol/L urea. AR and ß-actin probes (20,000 cpm each) and 5 µg total cellular RNA samples were coprecipitated in 70% ethanol and resuspended in hybridization buffer. RNA was denatured at 85 C for 10 min, hybridized for 16 h at 45 C, and subsequently digested in 10 mmol/L Tris-HCl (pH 7.5), 300 mmol/L NaCl, and 5 mmol/L ethylenediamine tetraacetate containing 1500 U/mL RNase T1 (Ambion, Austin, TX) at 37 C for 1 h. RNase activity was extinguished by a 15-min incubation at 37 C after the addition of 10 µL 10% SDS and 2 µL 20 mg/mL proteinase K followed by phenol-chloroform extraction. RNA was precipitated and separated on a 7 mol/L urea-PAGE gel. Gels were dried and exposed to x-ray film with Cronex intensifying screens at -70 C for autoradiography for 24 h.

Specific AR and ß-actin mRNA signals were quantitated after 3- to 6-h exposure of gels to a ß-sensitive PhosphorImager (Molecular Dynamics, Sunnyvale, CA). To facilitate direct comparison results from separate gels, RNase protection assays for each experiment were run using the same preparation of cRNA probes, thus with the same specific activity. Molar ratios were determined by correcting AR and ß-actin signals derived from the PhosphorImager for differences in specific activity and relative mass of the respective cRNA probes. In vitro transcribed AR cRNA probe was not hybridized to aldehyde reductase cDNA plasmid, confirming the specificity of the probe to AR mRNA. The interassay coefficient of variation of the AR RNase protection assay was 8.3%.

Clinical chemistry methods

Glyc Hgb was measured using an ion capture assay for quantitative measurement of the percent glycosylated hemoglobin, run on an Abbott IMX (Abbott Laboratories, North Chicago, IL). The procedure is a boronate affinity binding assay and detects all glycated hemoglobin species. The assay has a strong linear correlation with hemoglobin A1c-specific methods (32). Serum and urinary creatinine were measured on a Boehringer Mannheim/Hitachi 737 analyzer (Boehringer Mannheim, Indianapolis, IN; Hitachi, Tokyo, Japan), using a kinetic alkaline picrate modified Jaffe’s reaction (33). Urinary protein was measured on a Boehringer Mannheim/Hitachi 717 analyzer by a direct method that shows similar reactivities to albumin and globulin and has no interference from magnesium ions (34).

Statistical analysis

Statistical analyses were performed with SAS. To explore the hypothesis that heterogeneity of AR gene expression exists, we computed the mean, median, and 95% CI for each group. Values between groups were compared using ANOVA for normally distributed data and ANOVA for ranks (Wilcoxon rank sum test) for data that were not normally distributed. When differences were identified, we used multiple range tests to locate the differences. Multiple linear regression was used to test for the association of elevated AR/ß-actin molar ratios with KDDM. The general linear models procedure was used to test for an association between AR/ß-actin levels and age, gender, ethnicity, Glyc Hgb, serum creatinine, and UPCR. The least square mean of the AR/ß-actin molar ratio was calculated, adjusting for age, gender, and ethnicity. Results were considered statistically significant when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Human subjects

We studied 45 men and 36 women, aged 45 \ 12 yr (mean \ SD), ranging from 23–74 yr (Table 1Go). Although ANOVA indicated that the age difference among the four groups attained statistical significance (P = 0.045), the Student-Newman-Keuls test did not identify any pairwise comparisons between groups as being statistically significant (P = NS). However, the mean age (49 yr) for the combined groups with kidney disease (groups III and IV) was higher than that for the combined groups without kidney disease (groups I and II; P < 0.01). The body mass index and Glyc Hgb levels, respectively, were similar in groups II and III (P = NS). The mean arterial pressure was higher in group III than in group IV (P < 0.05). The durations of diabetes were similar in groups II and III (P = NS). Serum creatinine and UPCR, respectively, were similar in groups III and IV (P = NS).


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  		Table 1. Clinical characteristics of the study groups

 
AR/ß-actin molar ratios

We used serial dilutions of human kidney RNA to establish the linearity of the AR and ß-actin assays (Fig. 1Go). Data are expressed as AR/ß-actin molar ratios to control for the amount of RNA loaded. The molar ratio was constant (0.067 \ 0.005) over the range of mRNA concentrations evaluated. The molar ratio in PBMC obtained from normal subjects (0.045 \ 0.028) was approximately 30% of that in normal human kidney (P < 0.01), consistent with the relative abundance of AR mRNA and protein (25). The adjustment of AR mRNA for differences in ß-actin was necessary due to differences in RNA yields between samples.



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  		Figure 1. RNase protection assay for human AR and ß-actin mRNA. Human kidney and PBMC RNA protect antisense probe fragments of 222 and 129 nucleotides, corresponding to AR and ß-actin, respectively. The linearity of the RNase protection assay was established using serial dilutions of human kidney RNA containing 5, 2.5, 1.25, and 0.625 µg total RNA in lanes 1–4, respectively. Negative control hybridization with 5 µg transfer RNA (lane 5) and undigested AR and ß-actin probes (lanes 6 and 7) are included. Two representative samples of PBMC RNA (5 µg total cellular RNA/lane) from each group are shown.

 
The levels of AR expression in the four groups of volunteers are shown in Fig. 2Go and Table 2Go. The general linear models analysis revealed no significant association between molar ratios and age (P = 0.63), gender (P = 0.080), or ethnicity (P = 0.25) for the study population as a whole. There was a significant association between molar ratios and group (P < 0.0001). The mean AR/ß-actin mRNA levels, adjusted for age and gender, were similar in groups I and II (P = 0.085; P = NS). All other pairwise comparisons of molar ratio between groups were statistically significant. The molar concentrations of AR and ß-actin, quantitated by a PhosphorImager, are expressed as a percentage of the normal value and as the molar ratio (Fig. 2Go). Among diabetics, molar ratios were approximately 2-fold higher in group III than in group II. Molar ratios in group III were also higher than those in group I (P < 0.01) and group IV (P < 0.001). Diabetics without nephropathy (group II) had molar ratios similar to those observed in normal subjects (group I; P = NS). The level of AR expression observed in PBMC in diabetics with KDDM (group III) was approximately 4-fold higher than that in nondiabetics with kidney disease (group IV; P < 0.01). Molar ratios in group IV were lower than those in group I (P < 0.05) and group II (P < 0.05). Therefore, the relationship of AR/ß-actin molar ratios to renal disease was different in the diabetics from that in the nondiabetics.



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  		Figure 2. Data summary. Molar concentrations of AR and ß-actin quantitated by a PhosphorImager in the four groups of patients, as a percentage of the normal value (left axis) and as the molar ratio (right axis). I, Normal subjects; II, diabetics without nephropathy; III, diabetics with overt nephropathy; IV, nondiabetics with kidney disease. Data are expressed as means (±SEMs).

 

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  		Table 2. AR/ß-actin levels in the study groups

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have previously demonstrated the presence of regulatable AR gene expression in renal cortex. The present study extends these observations and demonstrates that the level of AR expression in PBMC obtained from IDDM patients with KDDM is increased compared with that in normal subjects, patients with IDDM and no evidence of nephropathy, and nondiabetics with kidney disease. These results support the hypothesis that regulated changes in AR gene expression modulate the risk for KDDM. In contrast, among nondiabetics, the lowest levels of AR expression were observed in volunteers with kidney disease. The explanation for the difference in the relationship of AR expression to kidney disease in diabetics vs. nondiabetics is not known. It is possible that the development of proteinuria and/or azotemia in nondiabetics decreases AR expression. In contrast, among diabetics, those with high AR expression may be more likely to develop kidney disease than those with low AR expression. A high level of expression persists in these patients despite the onset of proteinuria and/or azotemia.

The etiology of the higher AR mRNA levels observed in KDDM in the present study is uncertain. A selection process may be operative in vitro that favors the survival of PBMC with high or low levels of AR expression. Alternatively, changes in the stability of AR mRNA may contribute to the differences in the AR mRNA levels observed. However, recent evidence suggests that alterations in AR activity most likely reflect either heterogeneity of gene expression or the presence of significant polymorphism of the structural AR gene. Structural polymorphism could lead to alterations in protein structure and activity, which may result in a disparity between levels of AR-mRNA and AR-IRP. Ko et al. reported an association between the AR gene polymorphism and early-onset diabetic retinopathy in NIDDM patients among the Chinese population in Hong Kong (35). Specifically, they described the association of a specific allele (Z-2) of the dinucleotide repeat sequence located near the promoter region of the AR gene. We recently reported preliminary evidence that KDDM in Hispanics is associated with the Z-2 allele and high AR mRNA levels (36). Similarly, Hessom reported the association of KDDM and the Z-2 allele in Caucasians with KDDM (37). However, the results of the present investigation and other cross-sectional studies (35, 36, 37) do not establish causation. Increased AR expression may merely segregate with KDDM rather than have a role in its pathogenesis. The establishment of causation will require a prospective longitudinal study.

Absolute AR and ß-actin levels were widely variable within and between groups. Therefore, the high AR/ß-actin ratios observed in group III could reflect an increase in AR mRNA and/or a decrease in ß-actin mRNA. However, as ß-actin is constitutively expressed in PBMC, our results probably reflect increased AR expression. The duration of diabetes may modulate AR expression. Hyperglycemia increases flux through the polyol pathway; therefore, the effect of hyperglycemia on AR expression may increase with time. However, in the present study, the effects of both hyperglycemia and duration of diabetes on AR expression appear modest. AR/ß-actin ratios were similar in groups I and II, and the durations of diabetes were similar in groups II and III.

Transgenic mice, overexpressing the AR gene, may have an increased susceptibility to polyol-dependent complications (38, 39). Yamaoka et al. (40) investigated pathologic changes in transgenic mice with human AR cDNA driven by the murine MHC class I molecule promoter. Human AR mRNA was present in all tissues tested. However, as glucose feeding failed to increase renal sorbitol content, the functional integrity of the polyol pathway in this model is uncertain. Moreover, histopathological examination of the kidney revealed multiple thrombi and fibrinous deposits, but no evidence of glomerular hypertrophy or an increase in mesangial matrix. Lee et al. (39) recently demonstrated that overexpression of AR in lens epithelial cells of transgenic mice leads to polyol accumulation and the formation of sugar cataracts. When the sorbitol dehydrogenase-deficient mutation is also present in this model, there is greater accumulation of sorbitol and further acceleration of cataract formation.

Studies in rats with streptozotocin-induced diabetes (STZ-D) have linked the polyol pathway to the morphological and hemodynamic changes characteristic of KDDM (27, 41). The polyol content of glomeruli is increased 10-fold 6 weeks after the induction of STZ-D (42). Administration of AR inhibitors (ARI) decreases the glomerular hyperfiltration and mesangial expansion observed in STZ-D rats (43, 44, 45). Human studies also support a role for AR in the pathogenesis of KDDM (21, 22, 23, 39, 43, 44, 45, 46). The administration of ponalrestat (45) and tolrestat (46) to IDDM patients decreases the glomerular filtration rate and the urinary protein excretion rate. ARI administration normalizes RBC sorbitol in vivo in patients with IDDM (44).

Additional studies are necessary to assess the relationship between AR expression in PBMC and microdissected glomeruli. If there is a strong positive correlation, we will have a minimally invasive method to identify those diabetics who are at high risk for nephropathy. The presence of a strong positive correlation between AR and coll IV expression in microdissected glomeruli would provide a mechanistic link between the polyol pathway and the development of glomerulosclerosis. In summary, the present study suggests that the degree of AR gene expression in PBMC correlates with KDDM. If these observations are confirmed, an effort should be made to develop ARIs with improved tissue availability as well as AR antisense mRNAs to decrease AR expression in target tissues.


   Acknowledgments
 
The authors gratefully acknowledge the help of Dr. K. Gabbay for providing the human aldose reductase and aldehyde reductase plasmids, K. Kilpatrick for excellent technical assistance, and M. Lamey for expert secretarial assistance.


   Footnotes
 
1 This work was supported by Dialysis Clinic, Paul Teschan Research Fund (Nashville, TN); the Southern Arizona Foundation Research Fund (Tucson, AZ); Biomedical Research Support Grant S07-RR-05583–23 awarded by the Biomedical Research Support Program, Division of Research Resources, NIH; the University of New Mexico Clinical Research Center supported by National Center for Research Resources-General Clinical Research Center Grant RR-00997, NIH; and the Veterans Administration Research Service (Albuquerque, NM). Back

Received December 18, 1996.

Revised March 5, 1997.

Accepted April 2, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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