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Am J Physiol Renal Physiol 287: F586-F591, 2004. First published May 18, 2004; doi:10.1152/ajprenal.00414.2003
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How Genes Influence Renal Function and Disease

Estrogen receptor {alpha}-mediated events promote sex-specific diabetic glomerular hypertrophy

Alecia S. Lovegrove,1 Jianhong Sun,1 Karen A. Gould,2 Dennis B. Lubahn,3 Kenneth S. Korach,4 and Pascale H. Lane1

1Department of Pediatrics and 2Eppley Research Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198; 3Departments of Biochemistry and Child Health, University of Missouri, Columbia, Missouri 65211; and 4National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Submitted 26 November 2003 ; accepted in final form 12 May 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Sex differences in the incidence and progression of renal diseases suggest a protective role for estrogen. This study examined the role of estrogen receptor {alpha} (ER{alpha})-mediated events in normal and diabetic renal and glomerular growth. Wild-type and ER{alpha}-null mice (ERKO) were observed over 2 wk of streptozocin-induced diabetes. Blood glucose was monitored, and insulin was given daily to maintain levels of 250–350 mg/dl. Body weight, kidney weight, glucose, insulin, renal transforming growth factor-{beta}1, and glomerular area were examined for effects of sex, genotype, and diabetes. Genotype had no effect on glomerular or renal size in male mice regardless of metabolic state. Nondiabetic female ERKO mice had kidney weights approaching those of wild-type males and much greater than those of wild-type females (0.15 ± 0.04 vs. 0.11 ± 0.04 g; P < 0.001). When only diabetic mice were studied, sex and/or genotype showed no effect on renal weight. Diabetic female ERKO mice had smaller glomerular areas than wild types (2,799 ± 159 vs. 3,409 ± 187 µm2; P = 0.01). Glomerular areas were similar in diabetic wild-type and ERKO males (3,020 ± 199 vs. 3,406 ± 176 µm2). Transforming growth factor-{beta}1 levels, expressed as picograms per milligram total protein, were similar in diabetic wild-type and ERKO males (1.0 ± 0.6 vs. 0.9 ± 0.6). In diabetic females, wild types had significantly higher levels of this growth factor than ERKO mice (3.8 ± 0.7 vs. 1.1 ± 0.6; P = 0.005). ER{alpha}-mediated processes influence normal and diabetic renal and glomerular size, but only in female mice. These data do not support a protective role for ER{alpha}-mediated events in diabetic nephropathy.

transforming growth factor-{beta}; streptozotocin; mouse; genetically altered

THE DEVELOPMENT OF END-STAGE kidney failure due to any cause differs between males and females, with females being relatively protected from most disorders. In the United States, Caucasian men with Type 1 diabetes mellitus (DM) show a slightly higher rate of kidney failure from diabetic nephropathy than their female counterparts; however, this sex-mediated protection appears to be lost once menopause is reached, with an equal incidence of Type 2 DM-induced end-stage renal disease in postmenopausal women and age-matched men (30, 34). Even though the incidence of kidney failure is ultimately the same, women do appear to have a longer duration of Type 2 DM before the onset of renal replacement therapy (13). This has led some investigators to speculate that androgens may be detrimental to the kidney, whereas many others have focused on protective benefits of estrogens.

Many studies show a central role for transforming growth factor-{beta} (TGF-{beta}) in the initiation and progression of diabetic renal disease (1, 9). Renal mesangial and tubular cells produce TGF-{beta}, as do infiltrating cells. Mesangial and tubular cells respond to this growth factor with hypertrophy and biosynthesis of collagen and other matrix components. Hyperglycemia increases production and activation of TGF-{beta} in the kidney. By acting via an autocrine or paracrine mechanism, this growth factor contributes to diabetic renal and glomerular hypertrophy (31). Our lab previously showed that sexually mature male DM rats had increased expression and activity of TGF-{beta}1, along with increased glomerular hypertrophy, compared with prepubertal male DM rats (17). We have also demonstrated sex-related differences in the renal TGF-{beta}1 system in normal rats (16).

Given the central role of TGF-{beta}1 in diabetic nephropathy and our observations regarding puberty and sex differences in this system, it is tempting to speculate that sex steroids may influence diabetic kidney disease via the TGF-{beta}1 system. Two different forms of estrogen receptors are currently known to exist, estrogen receptor {alpha} and {beta} (ER{alpha} and ER{beta}) (22). Classical estrogen effects are mediated by ER{alpha} (4, 22). Recently, the kidney was shown to be one of the most ER{alpha}-regulated organs in the mouse (14). The roles of ER{beta} are less clear, and their presence in the kidney varies from study to study (5, 15, 23, 27, 28). The present study was designed to examine the effects of ER{alpha}-mediated events in early diabetic hypertrophy, using ER{alpha}-knockout (ERKO) mice, as well as the potential role of TGF-{beta}1 in these processes.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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Animals. Use of the animals in this study was approved by the Institutional Animal Care and Use Committee at University of Nebraska Medical Center. Experiments were performed using homozygous wild-type and ERKO mice of both sexes. At ~8 wk of age, DM was induced in half of each genotype by use of streptozocin, 200 mg/kg intraperitoneally on 2 consecutive days (35). The controls were injected with an equivalent volume of saline. DM was confirmed by glucose meter within 24 h of the second streptozocin injection. All diabetic mice received 1 unit of Ultralente insulin after confirmation of DM. All mice had ad libitum access to standard chow and tap water during the entire 2 wk of the study. Blood sugars of 300–500 mg/dl were maintained by blood glucose monitoring and subcutaneous injections of Ultralente insulin every 24 h. The dosage of insulin during the 2 wk of DM state ranged from 1.0 to 2.5 units per day. All mice were weighed before induction of DM, on the 8th day, and again on the 14th day after DM induction. On day 14, blood was obtained under isoflurane anesthesia by cardiac puncture. Both kidneys were excised. The left kidneys were weighed and snap-frozen in liquid nitrogen. The right kidney was hemisected and fixed in formalin for histological studies.

Biochemical studies. Random blood insulin levels were measured by ELISA (kit from Pierce, Rockford, IL). Blood glucose levels were determined colorimetrically (kit from Sigma, St. Louis, MO).

Protein studies. Protein was extracted from whole kidney by using a homogenization buffer containing Tris-buffered saline (pH 8.0), 1% Nonidet P-40, 10% glycerol, 10 µg/ml aprotinin, 1 µg/ml leupeptin, 10 mM PMSF, and 0.5 mM sodium vanadate. Levels of TGF-{beta}1 were measured by ELISA (Emax, Promega, Madison, WI). Total protein in the extracts was assessed by the Coomassie method (kit from Pierce). Results are expressed as picograms of TGF-{beta}1 per milligram of total protein.

Histological studies. Formalin-fixed kidneys were embedded in paraffin, sectioned at ~6-µm thickness, and stained with periodic acid Schiff. Glomerular area was determined by one observer, masked to the tissue identity. Consecutive fields of cortex were examined, beginning at the capsule and proceeding through the medulla. Profiles from the entire thickness of the cortex were examined for all animals. Digital images of profiles were captured, and the minimal convex polygon surrounding the glomerular capillary tuft was outlined and measured with Scion Image beta 4.0.2 (Scion, Frederick, MD). Final magnification was determined with stage micrometry. A minimum of 15 glomerular profiles were studied for each mouse. We have previously shown that glomerular area determined by this method is a reasonable proxy measurement of glomerular volume determined by strict stereological techniques (19, 20).

Immunohistochemistry studies. Kidney sections were mounted on coated slides and then treated with hydrogen peroxide and normal goat serum, followed by incubation with rabbit polyclonal antibody to the COOH terminus of human TGF-{beta}1 (Santa Cruz Biotechnology, Santa Cruz, CA). Anti-rabbit IgG conjugated with peroxidase was applied, followed by localization with 3-amino-9-ethylcarbazole (AEC; Chemicon International, Temecula, CA). Semiquantitative staining was rated on a spectrum from 0 to 4+ on two separate occasions by a single observer masked to the identity of the tissue (18).

Statistics. Two-factor ANOVA was performed for the major factors sex (male or female), genotype (wild-type or ERKO), and metabolic state (nondiabetic or DM). Significant results by ANOVA were followed by post hoc Tukey's tests. If data were not normally distributed, similar nonparametric tests were performed. Analyses were first performed on data from all 66 mice included in the study. Metabolic subgroups were then assessed using a similar ANOVA strategy for the sex and genotype.

All analyses were performed with SigmaStat 3.0 (SPSS, Chicago, IL). A P value <0.05 was considered significant for all comparisons.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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When the entire mouse population was studied, sex had significant effects on final mouse weight and kidney weight, with females having smaller body and kidney size as expected (Table 1). No effects of genotype could be demonstrated on any of the parameters when all 66 mice were studied. Metabolic state influenced final weight, weight change, kidney weight, glomerular area, glucose, and insulin levels as expected (Table 1). DM mice lost weight but had larger kidney weights and glomerular areas than nondiabetic animals. Glucose levels were higher and insulin levels lower in the DM mice (Table 1).


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  		Table 1. Major factor analysis for all mice

 
Subgroup analysis showed that all mice within the nondiabetic groups gained weight similarly (Table 2); neither sex nor genotype significantly influenced this parameter. In the DM mice, neither sex nor genotype significantly influenced final weight. All mice in the DM groups lost weight similarly (Table 2).


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  		Table 2. Factor analysis for metabolic subgroups

 
In nondiabetic mice, both sex and genotype influenced kidney weight; males and ERKO mice tended to have larger kidneys (Table 2). On further study, kidney weight did not vary with genotype in males, but female ERKO mice had greater kidney weights than wild types (Fig. 1). Kidney weights in female ERKO mice were not significantly different than those seen in males. Genotype and sex had no effect on kidney weight in the DM groups (Table 2 and Fig. 1).



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  		Fig. 1. Sex, diabetes, and estrogen receptor {alpha} influence kidney weight in mice. ERKO, estrogen receptor {alpha} knockout; NS, not significant.

 
Neither sex nor genotype influenced glomerular area in nondiabetic mice (Table 2 and Fig. 2). In the DM mice, no independent effects of sex or genotype were demonstrated, although there was significant interaction of these factors (Table 2). Among DM males, no significant difference was found in glomerular area between the wild-type and ERKO mice; however, the glomerular areas of the female wild-type mice were significantly larger than the female ERKO mice with DM (Fig. 2).



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  		Fig. 2. Sex, diabetes, and estrogen receptor {alpha} influence glomerular area in mice.

 
Neither sex nor genotype influenced blood levels of glucose or insulin among nondiabetic or among DM mice (Table 2). Renal levels of TGF-{beta} were studied, and no significant effects could be demonstrated for sex (males 3.1 ± 1.1 vs. females 3.0 ± 1.0 pg/mg) or genotype (wild-type 4.4 ± 1.1 vs. ERKO 1.7 ± 1.0 pg/mg) when all mice were studied. Metabolic state did alter TGF-{beta} (nondiabetic 4.8 ± 1.1 vs. DM 1.6 ± 1.0 pg/mg; P = 0.03), although not in the manner expected. When only nondiabetic mice were examined, no significant differences in TGF-{beta} were demonstrated for sex or genotype (Fig. 3). Both sex and genotype significantly influenced levels of the growth factor in DM mice with significant interaction; these differences were primarily due to higher levels of TGF-{beta} in female wild-type mice (Fig. 3). These values were expressed as picograms per milligram total protein in the kidney. Further analysis showed that levels of total protein were similar for all groups and that these differences among DM animals were due to changes in the measured levels of TGF-{beta}1 (wild-type males 3.9 ± 2.1; ERKO males 3.1 ± 2.1; wild-type females 12.9 ± 2.2; and ERKO females 3.7 ± 1.9 x 103 pg/ml). Immunohistochemistry for TGF-{beta} demonstrated no focal differences in distribution of this growth factor among these groups (Table 3. and Fig. 4).



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  		Fig. 3. Sex, diabetes, and estrogen receptor {alpha} influence renal cortical levels of transforming growth factor-{beta}1 (TGF-{beta}1) protein in mice.

 

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  		Table 3. TGF-{beta}1 immunohistochemistry for metabolic subgroups

 


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  		Fig. 4. Representative photomicrographs of TGF-{beta}1 immunohistochemistry. WT, wild-type.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
ER{alpha}-mediated events show sex-specific influences on renal and glomerular growth. Genotype had no influence on renal weight or glomerular size in male mice with or without DM. Genotype did influence kidney weight in nondiabetic females, with ERKO having larger kidneys than wild types. This parameter was nearly the same in ERKO females as it was in control males. Genotype did not alter kidney weight in diabetic animals. Although glomerular area was not influenced by genotype in nondiabetic mice, ER{alpha} did alter this parameter in DM females. ERKO DM females had glomerular areas similar to those of nondiabetic females, whereas wild-type females showed typical diabetic glomerular enlargement.

ER{alpha}-mediated processes appear to suppress normal renal growth in the female mouse. Most of the kidney is composed of tubules, so decreased renal weight suggests suppression of tubular growth. No alterations in glomerular area could be demonstrated in ERKO control mice, suggesting that this system plays less of a role in normal glomerular growth.

DM female ERKO mice were protected from diabetic glomerular enlargement. Hypertrophy and fibrosis are intricately linked, and all therapies that slow diabetic nephropathy also reduce glomerular size early in models of DM (36). ER{alpha}-mediated events may thus be detrimental, rather than protective, in diabetes because ERKO females were relatively protected from glomerular enlargement.

The hypothalamic-pituitary-gonadal axis has recently been characterized in ERKO mice (6). ER{alpha} is essential for negative feedback on production of luteinizing hormone, and females lacking this receptor show elevated plasma levels of this gonadotropin. The ovaries of these mice produce 17{beta}-hydroxysteroid dehydrogenase type III, an enzyme normally found only in the testes, that converts androstenedione to testosterone. ER{alpha}-null females have elevated plasma levels of androgens, similar to those seen in wild-type males (6). Both androgens and luteinizing hormone may promote renal growth, perhaps explaining the larger kidney weights in the nondiabetic female ERKO mice (2, 24, 25, 29, 37).

The ERs (ER{alpha} and ER{beta}) are distributed widely, with some organs having a predominance of one subtype and other tissues with equal expression (15, 22). Studies with ERKO mice have revealed that each receptor has similar but also unique roles in estrogen action (22). Expression of both receptors may alter signaling through ER{alpha}, whereas ER{beta} may specifically mediate anti-inflammatory effects (11, 12, 21, 22, 26, 33). ERs are often coupled into caveolae with nitric oxide synthase in endothelial cells, and both ER{alpha} and ER{beta} have been implicated in the function of a variety of vascular beds (3, 7, 8, 10, 32, 38). ER{beta}-deficient mice develop sustained hypertension, and their vascular smooth muscle cells show multiple abnormalities of ion channel function (38).

Whole kidney studies suggest the absence of ER{beta} in the postnatal kidney, even though it is present during embryonic development. Lack of ER{beta} in whole kidney preparations has been demonstrated in ER{alpha}-null mice such as used in our experiment (5), as well as in whole kidney from rats (15). Both receptors have been demonstrated in bovine kidney (27). This probably means that most tubular cells lack ER{beta} because they form the bulk of renal mass. ER{alpha} and ER{beta} have been found in murine glomeruli and in isolated mesangial cells (23, 28). Inhibition of collagen synthesis in mesangial cells is mediated to some extent through ER{beta} (23). Such focal expression of ER{beta} does not conflict with data from whole kidney preparations, because glomeruli constitute ~10% of the kidney and mesangial cells make up <3% of the renal mass.

It is possible that absence of ER{alpha} allows ER{beta} effects to predominate in our model. Estrogen may produce different effects via these receptors, and the mice used in these experiments produce estrogen (22). Our effects may be due to an altered estrogen response rather than an absent one. Alternatively, the differences demonstrated may be driven by the absence of ER{alpha} during renal development rather than during the actual experimental period. Further studies in ER{alpha}- and ER{beta}-null mice or with receptor type-specific pharmacological agents in wild-type mice may allow us to address these issues. Experiments that include ovariectomy or the use of antiandrogen drugs may allow us to examine the roles of androgen excess and ER{alpha} absence in this model.

In summary, these studies show that absence of ER{alpha} does not influence renal or glomerular size in male mice with or without DM. ER{alpha} appears to increase diabetic glomerular area in females but suppresses kidney weight in nondiabetic female mice. These data suggest a sex-specific role for ER{alpha}-mediated events in normal and diabetic renal growth, but they do not support a protective role for these processes in diabetic glomerulopathy.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by a grant from the John A. Wiebe, Jr., Children's Health Care Fund of Children's Hospital Foundation in Omaha, NE.


   DISCLOSURES
 
This work was presented at the Annual Meeting of the American Society of Nephrology, November 14, 2003, San Diego, CA, and published in abstract form (J Am Soc Nephrol 14: 126A, 2003).


   ACKNOWLEDGMENTS
 
We thank William J. Langer and Kay Devish for excellent technical assistance in the performance of these experiments.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. H. Lane, Dept. of Pediatrics, 982169 Nebraska Medical Ctr., Omaha, NE 68198-2196 (E-mail: phlane{at}unmc.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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