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【关键词】 hypertension
Center for the Study of Sex Differences and Departments of Medicine and Physiology and Biophysics, Georgetown University, Washington, District of Columbia
Departments of Science and Technology, Biophysics, and Medicine and Odontostomatology, University of Genoa, Genoa, Italy
ABSTRACT
Renal injury is greater in male compared with female rats after renal wrap (RW) hypertension. We investigated the role of gonadal steroids in the sex differences in RW disease severity in male (M) and female (F), castrated (Cast), and ovariectomized (OVX) rats and after dihydrotestosterone (DHT) and 17-estradiol (E2) treatment. Male castration attenuated the severity of RW-induced glomerulosclerosis (GS) [GS index (GSI): RW-M, 2.1 ± 0.2; RW-Cast, 1.3 ± 0.2; RW-Cast+DHT, 2.4 ± 0.4], mean glomerular volume (MGV; μm3 x 106: RW-M, 1.9 ± 0.1; RW-Cast, 1.45 ± 0.15; RW-Cast+DHT, 1.91 ± 0.15), tubular damage, and proteinuria (mg/day: RW-M, 130 ± 8; RW-Cast, 105 ± 5; RW-Cast+DHT, 142 ± 9), whereas DHT treatment abrogated these effects. Ovariectomy increased the GSI (RW-F, 0.69 ± 0.05; RW-OVX, 1.2 ± 0.1; RW-OVX+E2, 0.65 ± 0.05), tubular damage, and MGV (μm3 x 106: RW-F, 1.0 ± 0.06; RW-OVX, 1.5 ± 0.05; RW-OVX+E2, 0.96 ± 0.06), whereas E2 treatment prevented these effects. Furthermore, DHT treatment of RW-OVX animals exacerbated the GSI (1.9 ± 0.19), MGV (1.7 ± 0.2 x 106 μm3), and proteinuria (171 ± 21 mg/day) even further. Our data show that the lack of E2 and presence of androgens contribute to progressive renal disease induced by RW hypertension, suggesting that gonadal steroid status is an independent factor in the greater susceptibility men exhibit toward hypertension-associated renal disease compared with women.
testosterone; 5-dihydrotestosterone; 17-estradiol; sexual dimorphism
AS EARLY AS 1846, BRIGHT (4) noted that patients with renal disease develop hypertension and in 1923, Vohard (25) recognized the "vicious circle" in postulating that hypertension causes renal insufficiency. Direct evidence of hypertension causing renal disease arises from studies in patients with glomerulonephritis (23) and diabetic nephropathy (5), in which a genetic predisposition to hypertension increases the risk of developing renal disease, and from clinical trials showing that antihypertensive treatments slow the progression of renal disease (13).
We have recently shown that renal pathology develops in the 1-kidney, figure-8 renal wrap (RW) model of experimental hypertension and that male rats exhibited a greater degree of renal damage than the females 9 wk after RW surgery despite similar degrees of hypertension and renal function (11). Markers of renal injury, including proteinuria, mean glomerular volume (MGV), glomerulosclerosis (GS), and tubular damage, were greater in RW males compared with RW females, whereas mean arterial pressures (MAP) and glomerular filtration rates (GFR) were not detectably different between the sexes. These data suggested that the sex of the animal is an independent factor contributing to the degree of renal disease progression in RW hypertension.
These sex differences in renal disease severity reflect clinical studies indicating that the progression of renal disease is more rapid in men compared with women. Men exhibit a faster decline in renal function compared with women in nondiabetic renal disease, polycystic kidney disease, membranous nephropathy, and IgA nephropathy (15). In this study, we determined the role of gonadal steroids in renal disease severity in RW hypertension. We investigated the effect of male castration and female ovariectomy 9 wk after RW hypertension on MAP, GFR, and parameters of renal injury, including proteinuria, MGV, glomerulosclerotic index (GSI), and tubular damage. We also determined the role of androgens and estrogens in renal disease progression by investigating the effects of DHT in castrated males as well as E2 treatment in ovariectomized females. Last, we treated both sham-operated ovariectomized and RW-ovariectomized rats with DHT to determine whether androgens accelerate disease progression in females.
EXPERIMENTAL PROCEDURES
Animal maintenance. Sprague-Dawley female and male rats (78 wk old) were purchased from Harlan (Madison, WI) and maintained on a phytoestrogen-free normal-salt diet (NS; 0.4% NaCl; Harlan) with free access to water.
Animal surgeries, hormone treatment, and body weights. Under isoflurane anesthesia, the testis was removed in the male castration group (Cast), and the ovaries were removed in the ovariectomized (OVX) group. Administration of DHT (50 mg), E2 (0.6 mg), or vehicle was accomplished by implanting 60-day release pellets (Innovative Research, Sarasota, FL) subcutaneously in the dorsal region. For the control male (M) and female (F) groups, the testes or ovaries were visualized but not removed. In the RW animals, the right kidney was removed while the contralateral kidney was tied using 2.0 silk thread (RW-M, n = 8; RW-Cast, n = 10; RW-Cast+DHT, n = 11; RW-F, n = 8; RW-OVX, n = 21; RW-OVX+E2, n = 15; RW-OVX+DHT, n = 10), whereas in sham controls (Sham-M, n = 6; Sham-Cast, n = 10; Sham-Cast+DHT, n = 10; Sham-F, n = 6; Sham-OVX, n = 16; Sham-OVX+E2, n = 12; Sham-OVX+DHT, n = 6) both kidneys were visualized but not removed or wrapped (10). Body weights were determined at 0, 3, 6, and 9 wk postsurgery.
Blood pressure measurements and blood sampling. Nine weeks after sham or RW surgeries, all rats were anesthetized with Inactin (100 mg/kg, Sigma) and placed on a heated table to maintain body temperature at 37°C. A tracheotomy was performed to allow spontaneous breathing. A catheter was placed in the carotid artery for blood pressure measurements using a Blood Pressure Analyzer (Digi-Med, Louisville, KY) and for blood sampling. At the time of death, blood was collected in ice-cold Vacutainer tubes (Becton Dickinson) containing heparin sulfate. Samples were centrifuged at 2,000 g for 10 min, and the plasma (supernatant) was removed and frozen at 20°C for hormone assays.
Steroid hormone levels. Plasma testosterone and E2 levels were determined by radioimmunoassay (Coat-A-Count total testosterone, Coat-A-Count E2, Diagnostic Products, Los Angeles, CA). DHT was determined by ELISA (Alpha Diagnostics, San Antonio, TX).
GFR. Serum and urinary creatinine levels were measured with a creatinine autoanalyzer (Creatinine Analyzer 2, Beckmann Instruments) 9 wk after sham or RW surgeries in all animal groups. Creatinine clearance [per 100 g body wt (BW)] was calculated on the basis of 24-h urine collection. Plasma standards were run to ensure chromagen interference was minimal in these samples.
Urine protein excretion. Rats were placed in metabolic cages for determination of 24-h urinary protein excretion rates using the Bradford method (3).
Histology preparation. After 9 wk, rats were anesthetized with Inactin (100 mg/kg). Kidneys were fixed in 10% formaldehyde and embedded in 2-hydroxyethyl-methacrilate (Technovit 7100, Kulzer, Wehrheim, Germany) to minimize tissue distortion associated with paraffin embedding. Renal tissue was cut into 2-μm sections and stained with hematoxylin and eosin (for general morphological examination), periodic acid-Schiff (PAS; for assessment of basement membrane changes), or Masson’s trichrome stain (for demonstration of collagen deposition). PAS-stained sections were examined using a Nikon Eclipse E600 light microscope.
Morphological analysis. A custom-made, C language macro was written to measure the area of glomerular tuft profiles with the Optimas 6.5 image-analysis system (MediaCybernetics, Silver Spring, MD). The areas of at least 100 glomerular tuft profiles/kidney were measured. The glomerular tufts considered were subsequent unselected occurrences falling in the observation field of the operator, who moved the stage in a serpentine fashion from the outer to the juxtamedullary cortex. The MGV was estimated from the harmonic mean of the profile areas as previously described (14).
Renal pathology. All specimens were examined by a pathologist (C. Pesce) blinded to the group assignment of the experimental animals. One hundred glomeruli per section were assessed, and the degree of glomerular sclerosis was graded on a scale of 04 [0 (normal glomeruli); 1, sclerotic area up to 125% (minimal sclerosis); 2, sclerotic area 2650% (moderate sclerosis); 3, sclerotic area 5175% (moderate-severe sclerosis); and 4, sclerotic area 76100% (severe sclerosis)]. The GSI was calculated using the following formula: GSI = (1 x n1) + (2 x n2) + (3 x n3) + (4 x n4)/n0 + n1 + n2 + n3 + n4, where nx is the number of glomeruli in each grade of GS. The degree of diffuse GS and nodular GS was graded on a scale of + to ++++ [, (normal); +, affected area <125%; ++, affected area 2650%; +++, affected area 5175%; ++++, affected area 75100%]. The degree of tubulointerstitial fibrosis was defined as tubular atrophy or dilatation, deposition of ECM, and interstitial cell proliferation and was assessed in Masson’s trichrome-stained sections. The degree of tubulointerstitial fibrosis was graded on a scale of + to ++++ [, (normal); +, affected area <125%; ++, affected area 2650%; and +++, affected area 5175%; ++++, affected area 75100%]. The relative degree of tubulointerstitial fibrosis was determined by the degree of tubular atrophy or dilatation, deposition of ECM, and interstitial cell proliferation and was assessed in Masson’s trichrome-stained sections.
Statistics. Data are expressed as means ± SE. The statistical significance of the differences between groups was determined by two-way ANOVA, followed by Student-Newman-Keuls post hoc tests. Differences were considered significant at P < 0.05.
RESULTS
Gonadal steroid levels. RW surgery had no significant effects on testosterone and DHT levels in either the male or female animal groups, whereas RW consistently reduced E2 levels in both males and females to varying extents (Table 1). Male castration markedly decreased testosterone and DHT levels by >97% but had no effect on plasma E2 levels. Ovariectomy markedly reduced estradiol levels by about fourfold. The antibody used to measure testosterone cross-reacts with DHT by <4% and with estradiol by <0.02% (Diagnostic Products). Accordingly, DHT treatment in castrated males and OVX females did not have any significant effects on plasma testosterone levels. In contrast, the antibody to DHT cross-reacts with testosterone by 8.7% (Alpha Diagnostics), and thus DHT measurements can include some degree of testosterone. DHT treatment of castrated males and OVX females markedly increased DHT levels by about fivefold. E2 treatment of OVX females increased estrogen levels by >10-fold and were similar to peak physiological levels of estrogen (8). Noncastrated males had at least 30-fold higher levels of testosterone than females, whereas non-OVX females had at least 4-fold higher levels of plasma estrogen than males.
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MAP. Castration and ovariectomy had no effect on MAP in the sham animal groups, nor did DHT or E2 treatment, and no differences in MAP were observed among the Sham-M, Sham-Cast, Sham-Cast+DHT, Sham-F, Sham-OVX, Sham-OVX+E2, and Sham-OVX+DHT animal groups (Table 2). As shown before (11), RW significantly increased MAP in male and female animals by 30 mmHg. Male castration and female ovariectomy had no detectable effects on MAP in the RW animal groups; DHT or E2 treatment was also without effect; no differences in the degree of hypertension were observed among the RW-M, RW-Cast, RW-Cast+DHT, RW-F, RW-OVX, RW-OVX+E2, and RW-OVX+DHT groups (Table 2).
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BW. BW was comparable within female (241 ± 2.4) and within male (276 ± 2.0) animal groups at the outset of the study; however, male rats weighed 15 and 48% more than the Sham-F group at the outset and end of the study, respectively (Table 2). Although BW increased in both sexes during the course of the 9-wk experiment, there was no effect of RW on female or male BW as found previously (11). Furthermore, castration and DHT treatment did not effect male BW; no differences in BW were observed among the Sham-M, Sham-Cast, Sham-Cast+DHT, RW-M, RW-Cast and RW-Cast+DHT or between the Sham-F and RW-F, Sham-OVX and RW-OVX, Sham-OVX+E2 and RW-OVX+E2, or Sham-OVX+DHT and RW-OVX+DHT animal groups. In contrast, ovariectomy increased BW; BW was 20 and 15% higher in the Sham-OVX and RW-OVX compared with Sham-F or RW-F groups, respectively. This OVX-induced weight gain was prevented by E2 treatment; no differences in BW were observed among the Sham-F, Sham-OVX+E2, RW-F, and RW-OVX+E2 groups. DHT treatment also had no effect on the OVX-induced weight gain; no differences in BW were observed among the Sham-OVX+DHT, Sham-OVX, RW-OVX, and RW-OVX+DHT animal groups.
GFR. Castration and ovariectomy had no effect on GFR in the sham animal groups; nor did DHT or E2 treatment have any effect; no differences in GFR were observed among the Sham-M, Sham-Cast, Sham-Cast+DHT, Sham-F, Sham-OVX, Sham-OVX+E2, and Sham-OVX+DHT animal groups (Table 2). Although RW significantly decreased GFR by 37- 40% in all male and female animals, as shown before (11), castration and ovariectomy had no significant effects on GFR in the RW animal groups; DHT and E2 treatment were also without effect; no significant differences in GFR were observed among the RW-M, RW-Cast, RW-Cast+DHT, RW-F, RW-OVX, RW-OVX+E2, and RW-OVX+DHT groups (Table 2).
Proteinuria. As shown before (11), RW surgery increased the degree of proteinuria in both male and female animal groups (Table 3). By 6 wk, proteinuria was significantly elevated in all male RW groups compared with the Sham males. In contrast, no significant differences in proteinuria were observed in female RW animals compared with Sham females. By 9 wk, proteinuria had worsened further and was significantly elevated in both males and females compared with their corresponding Sham groups (Table 3). At 9 wk, proteinuria was 6.8-fold higher in RW-M compared with Sham-M and 7.7-fold higher in RW-F compared with Sham-F animals. Male castration attenuated the degree of proteinuria in the RW animals; proteinuria was 19% less in the RW-Cast compared with RW-M group. DHT treatment reversed this protective effect of castration; no significant differences in urine protein were observed between the RW-Cast+DHT and RW-M animals. Proteinuria was 2.1-fold higher in the Sham-M compared with the Sham-F and 1.9-fold higher in the RW-M compared with RW-F group. Ovariectomy and E2 treatment had no effect on the degree of proteinuria; no differences in urine protein were observed among the Sham-F, Sham-OVX, and Sham-OVX+E2 animal groups or among the RW-F, RW-OVX, and RW-OVX+E2 groups. In contrast, DHT treatment in the Sham-OVX+DHT and RW-OVX+DHT groups increased urine protein by 2.6- and 2.7-fold compared with the Sham-OVX and RW-OVX animals, respectively.
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MGV. No significant differences in MGV were observed among any of the sham-operated animal groups including Sham-M, Sham-Cast, Sham-Cast+DHT, Sham-F, Sham-OVX, Sham-OVX+E2, and Sham-OVX+DHT (Table 3). As shown before (11), RW surgery increased the MGV in both the male and female animal groups; MGV was 2.2-fold higher in the RW-M compared with Sham-M and 1.3-fold higher in the RW-F compared with Sham-F rats. Male castration reduced the MGV in the RW animals; the MGV was 24% less in the RW-Cast compared with RW-M group. DHT treatment reversed this effect; no significant differences in MGV were observed between the RW-Cast+DHT and RW-M groups. Sex differences in MGV were noted as before (11); MGV was 1.9-fold higher in the RW-M compared with RW-F animals. Ovariectomy increased MGV in the RW-OVX animals by 1.5-fold compared with RW-F. E2 treatment prevented this increase; no significant differences in MGV were observed between the RW-OVX+E2 and RW-F groups. DHT treatment had no effect; no differences between the RW-OVX+DHT and RW-OVX groups were found.
Renal pathology. Male castration attenuated the renal injury induced by RW, whereas the degree of renal damage in the RW-Cast+DHT animals was indistinguishable from the RW-M group. Compared with all other groups (Figs. 1 and 2, Table 4), renal damage (assessed by GSI and the degree of tubular damage) was most severe in the RW-M (Fig. 1B, Table 4) and RW-Cast+DHT (Fig. 1F, Table 4) animals. Many glomeruli were enlarged and frequently showed PAS-positive deposits in the mesangium, mesangial expansion, and areas of segmental necrosis. There were proteinaceous deposits in Bowman’s space; some glomerular tufts showed sinechiae, and the capsule was associated with cellular proliferation. The tubules were dilated, and there were hyaline casts in the distal tubules.
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Ovariectomy exacerbated the renal pathology induced by RW in the female (Fig. 2D). The degree of renal injury in the RW-OVX rats was similar to that in the RW-Cast group (Fig. 1D), whereas the injury observed in the RW-OVX+E2 group (Fig. 2F) was indistinguishable from that in the RW-F animals (Fig. 2B). Milder lesions were observed in the RW-F (Fig. 2B) and RW-OVX+E2 (Fig. 2F) groups compared with the RW-M (Fig. 1B), RW-Cast+DHT (Fig. 1F), RW-Cast (Fig. 1D), and RW-OVX (Fig. 2D) animals. Focal mesangial deposits of PAS-positive material were found, but no segmental necrosis and only occasional hyaline casts were observed in the tubules. DHT treatment in RW-OVX+DHT (Fig. 2H) animals resulted in renal pathology that was similar to that in the RW-M (Fig. 1B) and RW-Cast+DHT groups (Fig. 1F). No differences in glomerular and tubular morphology were observed among the Sham-M (Fig. 1A), Sham-Cast (Fig. 1C), Sham-Cast+DHT (Fig. 1E), Sham-F (Fig. 2A), Sham-OVX (Fig. 2C), Sham-OVX+E2 (Fig. 2E), and Sham-OVX+DHT (Fig. 2G) groups.
DISCUSSION
In a previous study, we showed that male rats exhibit a greater degree of renal injury 9 wk after RW hypertension compared with females despite similar levels of MAP and renal function (11). Our current study extends these earlier findings by determining the role of gonadal steroids in the observed sex differences in susceptibility to renal damage induced by this experimental model of RW hypertension.
Male castration significantly attenuated the development of proteinuria and glomerular and tubular damage. The finding that DHT treatment of castrated males prevented these protective effects suggests that androgens contribute to the development of renal pathology and proteinuria in the RW hypertensive male. The exacerbating effects of androgens on renal injury in RW hypertension are similar to observations in other models of renal disease, including the unilaterally nephrectomized rat (7), adriamycin-induced nephropathy (17), and the spontaneously hypertensive rat (19), suggesting that androgen exacerbation of renal injury is a common mechanism in many causes of chronic renal failure (CRF). The fact that no significant differences in BW were detected among any of the male RW groups, including RW-M, RW-Cast, and RW-Cast+DHT, suggests that the potential anabolic effects of testosterone on protein intake made minimal contributions to the development of renal injury in this model. The finding that castration and DHT treatment had no significant effects on MAP and GFR suggests that testosterone levels are an independent factor in the degree of renal injury in the RW hypertensive male.
While male castration was protective, ovariectomy exacerbated the degree of glomerular and tubular damage in the RW hypertensive female. The fact that E2 treatment of OVX-RW females prevented the aggravating effects of ovariectomy on renal pathology suggests that estrogens protect against the development of glomerular and tubular damage. These findings in the RW hypertensive female are similar to some experimental models of renal disease. Ovariectomy aggravated the development of glomerulosclerosis in the rat remnant kidney (1). However, not all models of CRF show this same estrogen nephroprotective effect. Glomerular hypertrophy and glomerular injury were unchanged by ovariectomy and estrogen replacement in uninephrectomized female rats (14), and glomerulopathy induced by aging in the female Munich-Wistar rat was not affected by the presence or absence of estrogen (2). However, in obese Zucker rats (6) and in Nagase analbuminemic rats (12) administration of E2 to OVX females actually impaired renal function and led to profound GS. Taken together, these data indicate that estrogen protects or contributes to progressive renal disease depending on the cause of CRF.
As expected, the OVX rats gained greater BW than vehicle-treated intact or E2-treated OVX animals. These differences in BW may have led to differences in nephron-to-BW ratios, which may have contributed to the greater renal damage observed in vehicle-treated OVX rats compared with the E2-replete animals. However, differences in nephron-to-BW ratios are unlikely to be a major contributor to the nephroprotective effects of estrogen since mostly adipose tissue accumulates in the OVX animal rather than muscle mass. We chose not to clamp BW in all animal groups over the 9-wk period because reducing foot intake in the males and OVX animal groups would have conferred a greater confounding variable than the potential contribution of differences in nephron-to-BW ratios. The finding that ovariectomy as well as E2 and DHT treatments had no major effects on MAP and renal function suggests that gonadal steroids are independent factors contributing to renal injury in the RW hypertensive female.
The development of hypertension in the RW animal involves the renin-angiotensin system (RAS) because inhibitors of ANG II action prevented sodium-induced hypertension (9). Our laboratory and others have shown that estrogen reduces the number of AT1 receptors in many tissues, including the adrenal, kidney, and vasculature, and attenuates tissue responsiveness to ANG II (16, 18, 21). Thus part of the renoprotective effects of estrogen may be through reducing AT1 receptor-mediated ANG II action. Less is known regarding the effects of androgens on the activity of the RAS; however, Reckelhoff et al. (20) have shown that angiotensin-converting enzyme inhibitors reduced MAP in the intact and OVX female SHR and in the intact and castrated male SHR to similar levels in all groups, suggesting that the development of hypertension in the SHR is mediated by the RAS regardless of sex and gonadal steroids. Thus it will be of interest to investigate the effect of gonadal steroids on the RAS in the RW kidney in future studies.
Studies on the role of gonadal steroids in chronic renal disease are relevant to humans. While men have a greater incidence and rate of progression of hypertension-associated progressive renal disease than women, there is a growing population of women with end-stage renal disease who are either postmenopausal or exhibit estrogen deficiency. The complexity of contributory factors emphasizes the need for further study to fully understand the mechanisms underlying the sex differences and to determine whether new therapeutic strategies, including hormone replacement therapy, could be specifically targeted to benefit subsets of patients with different causes of progressive renal disease. In this regard, Szekacs et al. (24) demonstrated that hormone replacement therapy (estradiol and norgestrel) significantly reduced creatinine clearance and proteinuria in a small population of diabetic and hypertensive postmenopausal women. Furthermore, the development of selective estrogen receptor modulators and selective androgen receptor modulators may ultimately lead to novel therapeutic approaches to reduce the progression of renal disease by selectively retaining the estrogenic renoprotective effects or antagonizing the adverse effects of androgens (22).
In summary, we found that the sex steroids DHT and E2 contribute to the sex differences observed in RW-induced renal injury. Male castration attenuated the severity of proteinuria and glomerular and tubular damage, whereas DHT treatment prevented these protective effects of castration and aggravated the effects of renal injury in OVX females. Ovariectomy exacerbated the severity of glomerular and tubular damage, whereas E2 treatment protected against this injury. Together, these studies indicate that the lack of estrogen and the presence of androgens are independent factors that contribute to renal damage in RW hypertension.
GRANTS
This study was supported by American Heart Association Beginning Grant-in-Aid 0060205U and a National Kidney Foundation of the National Capital Area Grant-in-Aid to H. Ji and National Institutes of Health Grants HL-57502 and AG-19291 to K. Sandberg.
ACKNOWLEDGMENTS
The authors thank Drs. William Welch, Tina Chabrashvilli, and Christine Maric for critical review of the manuscript.
FOOTNOTES
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.
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