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Sex Differences in Renal and Cardiovascular Function: Physiology and Pathophysiology

Effect of sex hormones on renal estrogen and angiotensin type 1 receptors in female and male rats

Departments of ¹Physiology and Biophysics and ²Medicine and ³Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University School of Medicine, Washington, DC

Submitted 6 June 2006 ; accepted in final form 19 September 2006

	ABSTRACT

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Although the mechanisms are not understood, evidence suggests that 17-estradiol (E₂) confers protection from cardiovascular and renal complications in many diseases. We have reported that E₂ decreases angiotensin type 1 receptors (AT₁Rs) in different tissues and hypothesize that E₂ exerts tonic inhibition on AT₁Rs, reducing effects of ANG II. This study determined the effects of E₂ and dihydrotestosterone (DHT) on cortical estrogen receptors (ERs) and glomerular AT₁R binding in rats. Animals underwent sham operation, ovariectomy (Ovx) or orchidectomy (Cas) and were treated (Ovx ± E₂; Cas ± DHT) for 3 wk. Cortical ER protein was 2.5 times greater, and ER was 80% less in females vs. males (P < 0.01). Glomerular AT₁R binding was lower in females than males [4,657 ± 838 vs. 7,457 ± 467 counts per minute (cpm), P < 0.01]. Ovx reduced ER protein by 50%, whereas E₂ increased ER expression after Ovx. The decrease in cortical ER in Ovx rats was associated with a significant increase in AT₁R binding (6,908 ± 609 cpm), and E₂ prevented this increase. There was no change in ER or AT₁R binding following Cas ± DHT (25 mg) treatment, although Cas did elevate cortical ER (P < 0.01). Interestingly, the high dose DHT (200 mg) elevated ER 150% above intact levels and profoundly decreased AT₁R binding (1,824 ± 705 cpm, P < 0.001 vs. intact male). This indicates that under normal conditions, glomerular AT₁R binding is significantly greater in male than female animals, which may be important in development of cardiovascular and renal disease in males. Furthermore, E₂ regulates ER and is inversely associated with glomerular AT₁R binding, supporting our hypothesis that E₂ tonically suppresses AT₁Rs and suggesting a potential mechanism for the protective effects of estrogen.

kidney; 17-estradiol; dihydrotestosterone; testosterone; ovariectomy; castration; angiotensin II

ANG II has been implicated in many cardiovascular and renal disease states, such as hypertension and diabetic nephropathy (41). Indeed, both angiotensin-converting enzyme (ACE) inhibitors and AT₁R antagonists (ARB) are clearly effective in lowering blood pressure and attenuating the progression of diabetic nephropathy in humans (7, 30, 35). In the kidney, the major actions of ANG II are mediated through the AT₁R. Stimulation of angiotensin type 1 receptors (AT₁Rs) has been shown to increase intrarenal cell proliferation and matrix remodeling, as well as disrupt the medullary interstitial concentrating system (10, 21). Furthermore, ANG II has been shown to induce TGF- gene expression in cultured mesangial cells, and a subsequent increase in matrix deposition, a step that is integral to the development and progression of renal disease. Recent findings suggest that sex differences exist in the regulation of the AT₁R, and the development of renal disease (13, 22). We hypothesize that the interaction between sex steroids and ANG II function may contribute to observed sex differences in development and progression of renal and cardiovascular diseases.

In support of this concept, we and others have shown that E₂ decreases tissue levels of ANG II (34, 47) and ACE expression and activity in female rats (6, 33, 38). We have also shown that ovariectomy increases AT₁Rs in adrenal, pituitary, and uterine tissues compared with intact females, while E₂ in overiectomized (Ovx) rats prevents the Ovx-induced increase in AT₁Rs in those tissues (47, 48). We have also observed this effect of E₂ in canine adrenal, myocardium, liver, and glomeruli using dynamic PET measurements (25). In vitro, E₂ has also been found to decrease the growth-promoting actions of ANG II on vascular smooth muscle cells by inducing phosphatases, which may serve to reduce the response to vascular injury (37). These findings suggest that under normal conditions, E₂ tonically suppresses the effects of ANG II. This action could contribute to the "protective" effects of E₂ against the development of cardiovascular and renal disease. In sharp contrast to E_2, Leung et al. (17) found that testosterone increases AT₁R binding in epididymal cells, but whether this represents a tissue-specific response to the testosterone is not clear. Thus, while the effects of gonadal steroids on renal AT₁R activity are not completely understood, there is compelling evidence that the interactions of these important hormonal systems on the kidney are important in both health and disease and may account for the observed sex differences in susceptibility and rate of progression of vascular and kidney disease.

The purpose of the present study was to determine the effects of 17-estradiol and dihydrotestosterone on cortical renal ERs. In addition, the changes in ER protein expression were correlated with glomerular AT₁R binding in female and male rats.

	METHODS

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Hormone replacement. All procedures were approved by the Georgetown University Animal Care and Use Committee. Female Sprague-Dawley (S-D) rats (Harlan, Madison, WI) were obtained at 12–14 wk of age and randomly divided into treatment groups: sham (intact control, n = 6); ovariectomized (Ovx, n = 6), and ovariectomized with E₂ replacement (Ovx + E₂, n = 6). Animals were anesthetized (12% tribromoethanol), the ovaries were exposed via bilateral flank incision and excised. Sham-operated animals underwent flank incision and manipulation of the ovaries before the wound was closed. Immediately after surgery, the animals were given daily injections of E₂ (5 µg/day sc) dissolved in 100 µl corn oil or corn oil vehicle (injections were used as they produced end-organ results comparable to intact female rats). The animals were fed a phytoestrogen-free diet (Harlan) and given tap water ad libitum. After 21 days of treatment, the animals were weighed and anesthetized, and blood was collected via cardiac puncture for measurement of serum E₂ levels. Kidneys were snap frozen in liquid nitrogen for Western blot analysis and binding assays.

Male S-D rats (Harlan) were obtained at 12–14 wk of age and randomly divided into three treatment groups: sham (intact control, n = 6), castrated (Cas, n = 6), or castrated with dihydrotestosterone (DHT) replacement (Cas + DHT) (Innovative Research, Sarasota, FL; 25 mg/21 days pellet, n = 6), which produces end-organ responses comparable to intact males. An additional group of animals received high doses of DHT (200 mg, n = 6). The testicles were removed via a scrotal incision, while rats were under 12% tribromoethanol anesthetic. At the time of surgery, the DHT pellets (Innovative Research) were implanted on the lateral side of the neck between the ear and the shoulder. The animals were fed a phytoestrogen-free diet (Harlan) and tap water ad libitum. After 21 days of treatment, the animals were weighed and anesthetized, and blood was collected via cardiac puncture for measurement of plasma DHT levels. Kidneys were snap frozen in liquid nitrogen for Western blot analysis and binding assays.

Western blot analysis. The renal cortex was dissected from the frozen tissue, homogenized, and prepared for Western blot analysis on the Bio-Rad Criterion system using 10% gels. Protein concentration was determined by the Bradford method using bovine serum albumin as the standard (Bio-Rad Laboratories, Hercules, CA). Thirty milligrams of total protein was loaded in each lane, and after electrophoresis, the proteins were transferred to a nitrocellulose membrane (45, 46). The blots were then blocked in 5% nonfat milk in PBS/tris (PBST) at 4°C and then exposed to primary antibody [ER (1:1,000 dil) or ER (1:500 dil), Santa Cruz Laboratories, Santa Cruz, CA] for 2 h at room temperature on a shaking platform. Blots were washed in 1% PBST and then incubated with horseradish peroxidase (HRP)-conjugated goat anti-rabbit secondary antibody (1:10,000) (KPL, Gaithersburg, MD). Proteins were then detected by chemiluminescent peroxidase (Amersham, Buckinghamshire, UK) reaction and recorded on X-ray film. Relative density of bands was determined, normalized against a Coomassie blue protein band, and reported as arbitrary density units. Quantitative comparisons of male and female ER were made on the data from the same gels. At least three Western blot analyses were performed on each group of samples for both ER and ER. To compare male and female samples (and confirm measurements), we used four samples in each group per gel, and multiple gels were used to analyze all of the samples from each group.

AT₁R binding. Kidney glomeruli were isolated for AT₁R binding studies, as previously described (22). Protein concentrations of isolated glomeruli were determined by the Bradford method. To determine total binding, 5 µg of isolated glomeruli from each animal were placed in 12 x 75 glass test tubes. Either buffer (for total binding) or a saturating concentration of unlabeled ANG II (to assess nonspecific binding) was added to the tubes (in duplicate), and then I¹²⁵-labeled [Sar¹,Ile⁸] ANG II was added to all of the tubes. The cells were incubated at room temperature for 3 h and immediately followed by filtration through glass-fiber filters (Whatman GF/C, Hillsboro, OR) on a Brandel cell harvester, as previously described. Specific binding was defined as the total binding minus the nonspecific binding in counts per minute. Quantitative comparisons of male and female AT₁R binding were made on data from the same binding studies.

Statistics. Statistical analysis between groups was performed using two-way ANOVA, with Student-Neuman-Keul's post hoc tests. Analysis within groups was performed by Student's t-tests or one-way ANOVA with Student-Neuman-Keul's post hoc tests. All data is presented as means ± SE; significance was designated at P < 0.05.

	RESULTS

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Kidney, heart, and body weights are given in Table 1. Although the loss of estrogen with Ovx increased whole body weight, organ weights were not different from intact female controls. In contrast, the loss of testosterone in the male was associated with significantly lower kidney and heart weights. Kidney and heart weights in DHT-supplemented rats were not different from those in intact males.

DHT levels were also determined in male and female rats. DHT was significantly reduced in Cas compared with intact male rats (44 ± 5 vs. 2,025 ± 238 pg/ml in intact males, P < 0.05), and DHT replacement in Cas males increased circulating DHT compared with Cas male rats (321 ± 163 and 3,363 ± 1,106 pg/ml in 25 mg and 200 mg/21 day doses, respectively, P < 0.05 vs. Cas).

Sex differences in renal estrogen receptor regulation. Figure 1, A and B illustrate renal cortical ER and ER proteins in intact male and female rats (For comparisons between sexes made on same gels, see representative gel strips in Fig. 1C). Renal cortical ER protein expression was 2.5 times greater in female, compared with male rats. In contrast, ER expression was over four times greater in male compared with female cortex. Following Ovx, there was a 50% reduction (P < 0.01) in cortical ER expression compared with intact female rats, whereas there was no change in ER protein expression following Cas in male rats (Fig. 2A). Interestingly, while Ovx did not affect cortical ER protein expression, Cas significantly increased cortical ER in male kidneys by 30% (Fig. 2B).

View larger version (35K): [in this window] [in a new window]   Fig. 1. Sex differences in renal cortical estrogen receptor (ER) protein abundance in adult rats._A: cortical ER protein expression was significantly greater in female than male kidneys. B: cortical ER protein was significantly greater in male than female kidneys. C: representative gels for ER and ER, showing representative male and female comparisons (4 samples for each group). Protein from the same animals (n = 6, each sex) is analyzed in A and B. *P < 0.05 between male and female animals. Cas, castrated; Ovx, overiectomized.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Effect of gonadectomy on renal cortical ER protein abundance. A: Ovx reduced cortical ER protein abundance by 50%; Cas did not change ER protein expression. B: Ovx had no effect on cortical ER. In contrast, Cas increased ER protein expression in male animals. Representative blots of two samples from the Western blot analysis are shown over the corresponding group in the graph. *P < 0.01 vs. intact same sex; n = 6 analyzed in each group.

View larger version (24K): [in this window] [in a new window]   Fig. 3. Effect of E2 and dihydrotestosterone (DHT) replacement on renal cortical ER protein abundance. A: E2 replacement at 5 µg/day significantly increased ER protein abundance in Ovx female animals (*P < 0.01). B: DHT at a dose of 25 mg/21 days did not affect ER protein expression in Cas male animals; however, there was a 150% increase in ER protein expression in the renal cortex from animals given a high dose of DHT (200 mg/21 days). n = 6 analyzed in each group; *P< 0.01 vs intact male.

View larger version (16K): [in this window] [in a new window]   Fig. 4. AT1R binding in female and male glomeruli. Ovx increased glomerular ANG type 1 receptor (AT1R) binding by 50%, while E2 replacement prevented this increase. There was no change in AT1R binding in castrated rats treated with or without DHT (25 mg/21 days) compared with intact males. In sharp contrast, the high dose of DHT significantly reduced AT1R binding to levels lower than observed in intact female glomeruli. Glomerular samples are from the same animals as shown in Fig. 3; *P < 0.01 vs. intact female, #P < 0.001 vs. intact male and intact female; n = 6 analyzed in each group.

	DISCUSSION

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The current study found that the level of AT₁R binding was inversely related to ER protein expression (Figs. 3, A and B, and 4), and this was true even with the high dose of DHT (200 mg pellet), which increased ER and profoundly decreased AT₁R binding compared with intact controls. This finding was unexpected, as neither parameter was altered by castration or the lower dose of DHT. The finding is especially intriguing, as plasma estradiol levels appeared to be very high (which supported our findings of high cortical ER), despite the fact that DHT is not a substrate for aromatase. This suggests that very high circulating DHT may affect other hormones or systems (which could alter estradiol and ERs). Also, in the brain, DHT has also been shown to act through ER receptors to affect stress responses (19); this opens the possibility that under certain conditions, DHT might act through these receptors in peripheral organs; however, the potential physiological relevance is unclear and warrants further study.

Our studies also clearly demonstrate the sex differences in AT₁R binding in glomeruli from intact female and male rats. Although higher AT₁R binding was consistently observed in male kidneys in the presence or absence of physiological levels of DHT, intact and E₂-supplemented female rats had significantly lower AT₁R binding (Fig. 4) compared with males; Ovx brought binding up to levels observed in male glomeruli. This strongly supports the idea that E₂ limits the development of hypertension and renal disease through tonic inhibition of the AT₁R. Investigators have reported that Ovx significantly increases the density of glomerular (11, 12), and adrenal (12) AT₁Rs, as well as blood pressure in the Dahl salt-sensitive rat, compared with E₂-supplemented Ovx or intact rats. Harrison-Bernard et al. (11) have also demonstrated that AT₁R blockade prevents the increase in blood pressure in salt-sensitive Ovx rats. These findings further support the concept that loss of E₂ (as with age) increases AT₁R activity and contributes to the development of hypertension. This interpretation fits well with the finding that tissue responsiveness to ANG II is reduced in the presence of E₂ (31).

Whether the actions of E₂ and testosterone are tissue and/or disease specific or are more widespread remains to be determined; however, studies by our lab and others suggest that the degree of protection or damage may depend on the underlying physiological state. For example, in uninephrectomized rats, male but not female kidneys exhibit overt testosterone-mediated glomerular hypertrophy, tubular damage, and proteinuria (3, 4, 23), which is associated with increases in glomerular AT₁R density, and is prevented by ARB treatment (22). Li et al. (18) have also reported that testosterone contributes to the sex-related differences in cardiac hypertrophy observed in male guanylyl cyclase-A knockout mice. These findings suggest that under certain circumstances, testosterone upregulates renal AT₁Rs, as it has been shown to do in epididymal cell cultures (17). Thus, depending on the specific tissue and disease process, testosterone may promote disease. Interestingly, while the progression of disease in many forms of chronic renal failure (including membranous nephropathy, IgA nephropathy, and polycystic kidney disease) is clearly accelerated in men compared with women (24), this is not true for diabetes. In fact, in diabetes, the progression of hypertension and nephropathy is accelerated in women (14, 26, 40). Evidence is building that the sex differences in diabetic disease are related to estrogen and ER status. 17-estradiol levels are decreased in diabetic female rodents (16, 39, 42), and recent findings have also shown that ERs are significantly decreased in mesangial cells from female db/db mice (Type 2 diabetes model) compared with wild type (apparently by local IGF-I) (15), again supporting the notion that ER expression is altered in diabetes. Together with our findings, this further strengthens the concept that the loss of E₂ with menopause or in diseases, such as diabetes, predisposes women to a higher risk of developing ANG II-associated pathologies. In contrast, testosterone has been associated with increased disease progression.

In conclusion, these studies support and extend previous work by demonstrating that the E₂-replete rat has higher ER expression and lower AT₁R binding in the renal cortex compared with the intact male or the Ovx female. The inverse correlation between ER expression and glomerular AT₁R at a key site for development of renal pathology strongly supports the concept that renoprotection in the female occurs, in part, by the E₂-mediated attenuation of AT₁R activity in the kidney.

	GRANTS

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This work was supported by National Institutes of Health (NIH) Grant R01 DK064916 (to S. E. Mulroney), American Diabetes Association Grant (to C. Maric), and NIH Grant R01 HL57502 to K. Sandberg.

	FOOTNOTES

 

Address for reprint requests and other correspondence: S. E. Mulroney, Georgetown Univ. Medical Center, Box 571640, Washington, DC 20057 (e-mail: mulrones{at}georgetown.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.

^* These authors should be considered first authors.

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