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Nephrol Dial Transplant (2003) 18: 54–61 Estradiol is nephroprotective in the rat remnant kidney Balazs Antus1, Peter Hamar1, Gabor Kokeny1, Zoltan Szollosi2, Istvan Mucsi1,3, Zoltan Nemes2and Laszlo Rosivall1 1Department of Pathophysiology, Semmelweis University, Budapest, Hungary, 2Department of Pathology, MedicalUniversity, Debrecen, Hungary and 3First Department of Internal Medicine, Semmelweis University, Budapest, Hungary female sex hormones, such as estrogens, may be Background. Female sex hormones may influence responsible for the lower susceptibility of women to the progression of renal diseases. We therefore eva- luated the effects of estradiol on the development of Glomerulosclerosis and atherosclerosis may share glomerulosclerosis in a remnant kidney model.
common elements in their pathogenesis. It has been Methods. Ovariectomized or intact female Wistar rats suggested that the renoprotective effects of estrogens underwent 5u6 nephrectomy. Ovariectomized animals may be related to their effects on glomerular mesangial were treated with vehicle, 17b-estradiol alone or in cells in a manner analogous to the effects of estrogens combination with progesterone, intact rats received on vascular smooth muscle cells in atherosclerosis.
vehicle only. Twenty-four weeks after renal ablation, In support of this hypothesis, estradiol has been histological as well as molecular analysis were shown to suppress cellular proliferation as well as the synthesis of type I and IV collagen, and to inhibit trans- Results. Vehicle-treated ovariectomized animals deve- forming growth factor (TGF)-b- anduor platelet- loped severe proteinuria and glomerulosclerosis as derived growth factor (PDGF)-mediated type IV compared with vehicle-treated intact rats. In addition, collagen expression in mesangial cells [2]. Further- renal mRNA levels of platelet-derived growth factor-A more, estradiol induces the synthesis of matrix metallo- chain (PDGF-A) were increased. Estradiol replace- proteinases in mesangial cells, suggesting that estrogens ment reduced proteinuria, which was paralleled by a may limit glomerular scarring by increasing matrix diminished glomerular injury and reduced transform- ing growth factor-b1 (TGF-b1) and PDGF-A mRNA The renoprotective properties of estrogens, however, expression. In animals that received combined hor- have been recently challenged. Baylis et al. [4] reported mone treatment there were no significant differences in that age-related glomerulopathy in female rats is not proteinuria, creatinine clearance, renal histopathology influenced by estrogens. Similarly, Mulroney et al. [5] and growth factor mRNA levels compared with those demonstrated that ovariectomy has no effect on early measured in vehicle-treated ovariectomized rats. Serum development of glomerular hypertrophy and glomer- cholesterol and triglyceride levels were comparable ular injury in uninephrectomized female rats. Finally, between all groups during the whole follow-up period.
in obese Zucker rats and in Nagase analbuminemic Conclusions. The data suggest that estrogens protect rats, administration of estradiol impairs renal function against the development of glomerulosclerosis in the and induces profound glomerulosclerosis [6,7].
It has been argued that co-administration of pro- gesterone with estrogens can modulate the cardio- and Keywords: estradiol; glomerulosclerosis; growth factors; atheroprotective effects of estrogens. Some investiga- tors have observed a decrease in the beneficial effectsof estrogens [8], while other studies demonstrated noadverse effects of progesterone addition [9]. Never- theless, little information is available as to whether theaddition of progesterone to estrogens influences the Progression of chronic renal failure is slower in women effects of estrogens in renal injury.
than in men. Recently, it has been speculated that Thus, in the present study we investigated the role of estrogens in the development of progressiveglomerulosclerosis after subtotal renal ablation in Correspondence and offprint requests to: Dr Balazs Antus, Semmelweis female Wistar rats. Furthermore, we tested whether University, Department of Pathophysiology, Nagyvarad ter H-1089 Budapest, Hungary. Email: antbal@net.sote.hu co-administration of progesterone with estrogens # 2003 European Renal Association–European Dialysis and Transplant Association modulates the effects of estrogens on this process.
pressure (Hemosys, Experimetria, Hungary) was measured.
Finally, we studied whether growth factors such as Thereafter, rats were bled and the kidneys and the uteri TGF-b and PDGF, which are commonly associated were removed. Remnant kidneys were cut into two pieces.
with progressive glomerulosclerosis, are affected by One kidney sample was snap frozen in liquid nitrogen formolecular analysis, the other piece was fixed in buffered Fixed kidney tissues were embedded in paraffin and stained using haematoxylinueosin, periodic acid–Schiff (PAS) and Seven-week-old female Wistar rats (Charles River, Hungary) Masson’s trichrome methods. PAS reaction was performed weighing 160–200 g were used in these experiments. Animals to evaluate the extent of glomerulosclerosis. Glomerulosclerosis were kept under standard conditions and given free access was defined as the accumulation of extracellular matrix in to tap water, and the same amount of standard rat chow the mesangium. Collapse of capillaries and adhesion of obsolescent segments of Bowman’s capsule were frequently uweekuanimal). All experiments were approved by a governmental committee on animal welfare.
seen in the sclerosed glomeruli. Glomerulosclerosis wasevaluated according to the following scoring method: score0, normal glomerulus; score 1, mild segmental glomerulo- sclerosis affecting -25% of the glomerular tuft; score 2,moderate segmental glomerulosclerosis affecting 25 to 50% All rats were subjected to subtotal (5u6) renal ablation under of the glomerular tuft; score 3, diffuse severe glomerulo- sodium-pentobarbital (55 mgukg, i.p.) anaesthesia as des- sclerosis affecting )50% of the glomerular tuft. A mini- cribed previously [10]. Briefly, after removal of the right mum of 40 glomeruli per remnant kidney was examined, kidney, the left kidney was subtotally resected by removing and the mean of the glomerular scores was taken to from the cortex two-thirds of the weight of the resected right represent the severity of glomerulosclerosis for a given rat.
kidney. Special care was taken to avoid damage to pelvis The degree of tubulointerstitial fibrosis (tubulointerstitial and hilum. To stop bleeding, renal vessels of the left kidney damage index) was evaluated in trichrom-stained sections were clamped for 5 min in all operated animals including and graded according to the following scale: 0, no evidence ovariectomized and intact animals. The excised kidney tissue of interstitial fibrosis; grade 1, lesions involving -25% of was weighed on an analytic scale. The average reduction of the tubulointerstitial area; grade 2, lesions affecting 25– the total kidney mass was 74 " 1.4%.
involving )50% of the tubulointerstitial area. All histo-pathological evaluations were carried out by two indepen- dent observers (B. Antus and Z. Szollosi) blinded to the Following renal ablation a total number of 32 animals were randomly allocated into the following four experimentalgroups (ns8ugroup) according to gonadal status and hor-monal treatment: animals in the first group remained intact and received vehicle (INT). In the second, third and fourth Total RNA was extracted with Trizol (GibcouBRL, Life groups, rats were ovariectomized and treated with either 17b- Technologies, Germany) according to the protocol provided estradiol (E), 17b-estradiolqprogesterone (EqP) or vehicle by the manufacturer. Briefly, frozen tissues were mixed with (OVX). 17b-Estradiol (20 mgukg; Sigma, Sigma Aldrich, 1 ml Trizol reagent, homogenized, mixed with 0.2 ml chloro- Germany) and progesterone (10 mgukg, Sigma) were dis- form, and centrifuged at 12 000 g for 15 min at 48C. RNA, solved in sesame oil and administered subcutaneusly every from the aqueous phase, was precipitated with 0.5 ml second day (0.1 ml) until harvesting, similarly to our pre- isopropyl alcohol and centrifuged at 12 000 g for 10 min.
vious studies [11]. Vehicle-treated intact (INT) and ovar- iectomized (OVX) animals were given sesame oil alone. The centrifuged at 7500 g for 5 min and dried. RNA was reduction of the renal mass was similar between the groups dissolved in DEPC-treated water and stored at À808C.
(INT, 73.7 " 3.7%; OVX, 75.2 " 1.8%; E, 74.1 " 2.6% andEqP, 73.1 " 3.1%).
Reverse transcriptase–polymerase chain reaction RNA was amplified by reverse transcription (RT) with anOligo(dT)12–18 primer (Perkin-Elmer, Applied Biosystem, Every 4 weeks, body weights were measured and 24-h Germany) using 1 mg of total RNA added to 0.5 mg of urine samples were collected using metabolic cages and a primer. The reaction mixture contained: buffer solution urine-cooling system. Urine protein was determined nephelo- [TRIS hydrochloride (50 mM, pH 8.3); potassium chloride metrically, while serum cholesterol and triglyceride concen- trations were determined using a Reflotron analyzer (5 mM)], adenosine triphosphate, thymidine triphosphate, guanosine triphosphate and cytosine triphosphate each at a At week 24, serum as well as urine creatinine levels were concentration of 0.2 mM (GibcouBRL), 0.5 ml of 40 Uuml measured to determine creatinine clearance. Furthermore, of recombinant ribonuclease inhibitor (Perkin-Elmer) and serum 17b-estradiol and progesterone concentrations were 0.5 ml of 200 Uuml M-MLV reverse transcriptase (GibcouBRL).
measured by radioimmunassay using commercially available The reaction was allowed to proceed (428C, 1 h), then it kits (Immunotech, Izinta, Hungary). Animals were then was halted by heating the samples to 958C for 5 min Specific cDNA products corresponding to mRNA for weight, as well as the uterus weight-to-body weight ratio, TGF-b1, PDGF-A chain and b-actin were amplified using was significantly lower in vehicle-treated ovariecto- polymerase chain reaction (PCR) as described previously mized (OVX) animals as compared to vehicle-treated [10,11]. Briefly, 1 ml from RT reaction was taken for PCR, intact rats (INT) (Table 1). Estrogen replacement which was performed in PCR buffer [750 mM Tris–HCl, alone (E) or in combination with progesterone (EqP) pH 9.0, 200 mM (NH4)2SO4, 0.1% (wuv) Tween 20, 20 mM maintained uterus weight similar to animals with magnesium dichloride (Qiagen, Germany)] using 0.2 mM of each deoxynucleoside triphosphates, 1 mM of both primersand 2.5 U thermus Aquaticus (Taq) DNA polymerase(Qiagen). A Perkin-Elmer Thermal Cycler (Model 9600,Perkin-Elmer, Norwalk, CT) was used for amplification with the following sequence profile: initial denaturation at 948C By week 24, vehicle-treated ovariectomized animals for 3 min followed by 30–35 cycles (denaturing: 948C for developed increased proteinuria as compared to 30 s; annealing: 558C for 30 s; extension: 728C for 30 s) and ending with a final extension at 728C for 7 min.
versus INT 283.2 " 47.5 mgu24 h, P-0.05, ANOVA) The amplified PCR products were identified by electro- (Figure 1). Furthermore, serum creatinine levels were phoresis of 10 ml aliquots on 1.5% agarose gel stained with0.5 mg elevated and there was a trend towards a decreased uml of ethidium bromide. Specific products were visualized by UV transillumination and identified by size in creatinine clearance in these rats (Table 2). Estradiol relation to a 1 kb oligonucleotide DNA ladder (GibcouBRL).
replacement reduced both proteinuria (E, 286.4 " 39.1 Intensities of the specific bands were semiquantitated by versus OVX, 556.6 " 112.4 mgu24 h, P-0.05, ANOVA) densitometric analysis, and the ratios of the density of the and serum creatinine to approximately the same level specific bands to the bands of b-actin (internal control) were as in vehicle-treated intact rats. Similarly, the creati- nine clearance was better maintained in estradiol-treatedanimals as compared to vehicle-treated ovariectomized rats. Co-administration of progesterone with estradioltended to reduce the beneficial effects of estradiol both on Data are presented as mean " SEM. Parametric data were urinary protein excretion (E, 286.4 " 39.1 mgu24 h compared using one-way analysis of variance (ANOVA), versus EqP, 383.6 " 62.6 mgu24 h) and serum crea- followed by multiple pair-wise comparison according to the tinine, but these differences did not reach statistical Newman–Keuls test. Non-parametric data were tested using Kruskal–Wallis one-way analysis of ranks. A P value of-0.05 was considered significant.
Ovariectomy elicited a significant reduction of plasma 17b-estradiol levels (Table 2). Estradiol levelsin rats treated with estradiol alone (E) or in combina- tion of progesterone (EqP) were within the rangefor intact female rats reported in the literature [12]and were not significantly different from values for At the beginning of this study, body weights were throughout the estrus cycle) in the present study. One comparable between the groups (Table 1). At week 24, estradiol-treated rat with extremely high estradiol body weight was significantly higher in vehicle-treated levels ()300 pguml) was excluded from this study.
ovariectomized (OVX) rats compared to intact (INT) Ovariectomy also reduced serum progesterone con- or sex hormone-treated animals (E, EqP). Further- centrations (Table 2). Addition of progesterone to more, sex hormone-treated animals tended to have a estradiol treatment (EqP) resulted in plasma concentra- decreased body weight compared with intact rats.
tions of progesterone similar to those reported previously Atrophy of the uterus is considered to be a sensitive in the literature [12] or obtained in vehicle-treated indicator of the completeness of ovariectomy. Uterus intact animals (INT) in the present study.
Table 1. Body and uterus weight at the time of renal ablation and after 24 weeks aP-0.005 vs vehicle-treated intact animals (ANOVA).
bP-0.01 vs vehicle-treated intact animals (ANOVA).
cP-0.01 vs vehicle-treated ovariectomized animals (ANOVA).
Fig. 1. Changes in 24-h urinary protein excretion throughout the study. (*P-0.05 vs vehicle-treated intact animals; §P-0.05 vsvehicle-treated ovariectomized animals).
Table 2. Mean arterial blood pressure and serum values aP-0.05 vs vehicle-treated intact animals (ANOVA).
bP-0.01 vs vehicle-treated ovariectomized animals (ANOVA).
cP-0.01 vs vehicle-treated intact animals (ANOVA).
dP-0.005 vs 17b-estradiol-treated ovariectomized animals (ANOVA).
Mean arterial blood pressure seemed to be the diminished glomerular injury in these animals was highest in vehicle-treated ovariectomized animals, but accompanied by a significantly lower degree of the difference between the groups was not significant (Table 2). Similarly, lipid levels, both serum choles- Both glomerulosclerosis index and the degree of terol and triglyceride were comparable between the tubulointerstitial fibrosis were elevated in animals groups during the whole follow-up period (Figure 2A that received the combined sex hormone replace- and B). However, by week 24, cholesterol levels in all ment (EqP) as compared with those given estradiol treatment alone (E); however, these differences werenot statistical significant (Table 3). Similarly, neitherglomerulosclerosis nor tubulointerstitial fibrosis dif- fered significantly between animals that received the Glomerulosclerosis was significantly increased in ovar- combined hormone replacement (EqP) or vehicle iectomized vehicle-treated rats (OVX) as compared to intact rats (INT) (Table 3). Similarly, we noted asignificantly higher degree of tubulointerstitial fibrosis Glomerulosclerosis was significantly reduced in estradiol-treated animals (E) compared to vehicle- sion detected by semiquantitative PCR paralleled treated ovariectomized rats (OVX) (Table 3). The development of renal fibrosis (Figure 3). Accordingly, ovariectomy induced an ;2-fold increase in expres-sion of PDGF-A in vehicle-treated animals (OVX,2.1 " 0.3 vs INT, 0.9 " 0.1, P-0.01, ANOVA). TGF-b1 mRNA levels were also increased in vehicle-treatedovariectomized 1.4 " 0.2), however, these differences were not sig-nificant. Estradiol replacement reduced expression ofboth TGF-b1 (OVX, 2.7 " 0.4 vs E, 1.1 " 0.2,P-0.05, ANOVA) and PDGF-A (OVX, 2.1 " 0.3vs E, 0.6 " 0.1, P-0.005, ANOVA). Animals thatreceived estradiol in combination with progesteronetended to have elevated TGF-b1 (EqP, 1.5 " 0.5 vs E,1.1 " 0.2) and PDGF-A (EqP, 1.6 " 0.3 vs E,0.6 " 0.1) expression compared to estradiol-treated rats.
In this study we found that estrogen status plays animportant role in the progression of glomerulosclerosisafter subtotal renal ablation in female rats. Estrogendeficiency in gonadectomized females was associatedwith a rapid loss of renal function that was preventedby estradiol replacement. The data suggest thatestrogens are renoprotective in a model of chronicrenal injury.
Depending on the experimental setting, estrogens may exert various and even opposite effects on pro-gression of renal disease. In female hypercholester-olemic Imai rats, ovariectomy has been shown toaccelerate renal injury, while estradiol replacementattenuated this response [13]. Similarly, we demon-strated previously that estrogens ameliorate chronicallograft nephropathy in transplanted rat kidneys [11].
However, there are reports in contradiction with thesefindings. For example, Baylis et al. [4] reported thatage-related glomerulopathy is not influenced by estro-gens. It is possible that different mechanisms may beinvolved in glomerulopathy due to age compared withrenal ablation. For instance, glomerular hypertensionis known to play a central pathogenic role in theremnant kidney model, while this risk factor may beless important for age-dependent glomerular injury [4].
Development of compensatory renal growth and glo- Fig. 2. (A) Changes in serum cholesterol levels throughout the study.
merular damage in uninephrectomized female rats also (B) Changes in serum triglyceride levels throughout the study.
seems to be independent of estrogens [5]. However, Table 3. Histological characteristics of the remnant kidneys aP-0.05 vs vehicle-treated intact animals (Kruskal–Wallis test).
bP-0.05 vs vehicle-treated ovariectomized animals (Kruskal–Wallis test).
Fig. 3. TGF-b1 and PDGF-A chain mRNA expression in the remnant kidneys at the end of the study. (*P-0.05 vs vehicle-treated intactanimals; §P-0.05 vs vehicle-treated ovariectomized animals.) renal function is relatively well preserved after unine- to the more pronounced renal injury in ovariectomized phrectomy, thus conclusions concerning the role of rats. It is unclear whether this tendency in blood estrogens in a progressive fibrotic process cannot be pressure was due to the effects of estrogens, or was drawn from those experiments. Finally, in rat strains simply associated with the more pronounced renal with spontaneous hypertriglyceridaemia, estrogens pro- failure in these rats. Furthermore, it should be noted mote renal injury [6,7]. In these models, administra- that in our experiment blood pressure was measured in tion of estrogens causes further increases in lipid levels, anaesthetized rats. It is possible that the differences in which led to progressive renal injury. Wistar rats, blood pressure between the groups would have reached used in our study, are normolipidaemic and neither statistical significance, if blood pressure would have gonadal status nor estradiol treatment influenced lipid been measured in awake animals, for example, with parameters. Our data, therefore, do not support a telemetry. This technology, however, was not available role for lipids in the renal effects of estrogens.
It is well established that dietary protein intake Serum creatinine levels paralleled the marked histo- influences the development of renal disease. In our logical changes both in vehicle- and in estradiol-treated study, animals were offered the same amount of food animals. In contrast, creatinine clearance did not show during the whole follow-up. Therefore, differences in similar clear correlation with the histology. The reason renal injury between the groups cannot be due to for this discrepancy is not clear. However, creatinine various protein intake. Nevertheless, vehicle-treated clearance may be a somewhat inaccurate estimate of ovariectomized rats gained more body weight than renal function in rats due to the relatively high tubular vehicle-treated intact or all sex hormone-treated rats.
creatinine secretion. This may explain why differences Therefore, one may argue that nephronubody weight in creatinine clearance were not statistically significant mismatch is present and that may have contributed to the more marked renal damage in vehicle-treated The mechanism, by which progesterone tended to ovariectomized rats. However, since these animals reduce the beneficial effects of estrogen, is unclear.
accumulate mostly adipose tissue, but not muscle Progestins are known to exert partial androgenic mass, nephronubody weight mismatch may have had effects weakly binding to androgen receptors in various little effect on renal injury. Using a pair-feeding tissues, including the kidney [14]. As androgens protocol would have maintained body weight equal promote renal fibrosis [4,11], it is feasible that between the groups. However, in this case, protein activation of androgen receptors are responsible for consumption would have been different between the the effects of progesterone. Furthermore, interactions groups. Since we believe that in the reported setting between progesterone and estrogen or progesterone protein intake could have been a more important and angiotensin type I receptor expression [15] could confounder than nephronubody weight mismatch, we controlled protein intake, but not body weight in our Glomerular injury in the rat remnant kidney model has been generally attributed to an altered regulation As shown in Table 2, arterial blood pressure tended of matrix turnover by mesangial cells. Our data are in to be higher in vehicle-treated ovariectomized rats as accordance with previous findings demonstrating that compared to vehicle-treated intact animals. This estradiol may directly limit glomerulosclerosis by somewhat higher blood pressure may have contributed either inhibiting collagen synthesis or increasing the production of matrix metalloproteinases in mesangial be higher than therapeutic doses in humans. The reason for this difference is not clear, but variances Furthermore, a wide range of growth factors, between therapeutic doses in animal and human including TGF-b1 and PDGF have been implicated studies may perhaps be associated with differences in in the development of glomerulosclerosis [16]. TGF-b1 promotes matrix synthesis and inhibits its degradation In conclusion, we demonstrated that estradiol has a by several mechanisms, and is therefore one of the protective effect on the kidney during progressive most important mediators of tissue fibrosis [17].
glomerulosclerosis in the female rat remnant kidney Similarly, PDGF, apart from its strong mitogenic model. Further studies are clearly needed to assess the properties, stimulates production of various compo- potential applicability of these experimental findings in nents of extracellular matrix in human and experi- mental renal diseases [11,18]. Moreover, it has recentlybeen suggested that estrogens may have a direct atheroprotective effect through inhibition of TGF-b1 Research Foundations (OTKA 29260, 34409, F034498, ETT232 and PDGF-A expression in vascular smooth muscle and FKFP 316) and the Hungarian Kidney Foundation. Dr Mucsi cells [19]. As mesangial cells are phenotypically similar is a recipient of the Be´ke´sy Postdoctoral Scholarship from the to smooth muscle cells, we hypothesized that the Hungarian Ministry of Education, Dr. Hamar is a Bolyai ResearchFellow of the Hungarian Academy of Sciences. The skilful renoprotective effects of estradiol may be mediated, at assistance of Maria Godo at the Department of Pathophysiology, least in part, by its inhibitory effects on growth factor Semmelweis University and Agnes Kovacs at the 2nd Department synthesis in mesangial cells. Indeed, estradiol treatment of Internal Medicine, Semmelweis University was gratefully down-regulated the increased TGF-b1 and PDGF-A expression after ovariectomy, and this may havecontributed to a better outcome in this group. Theco-administration of progesterone, however, tended to reduce the beneficial effects of estradiol on expressionof TGF-b1 and PDGF-A that may be responsible for 1. Silbiger SR, Neugarten J. The impact of gender on the progression of chronic renal disease. Am J Kidney Dis 1995; the more pronounced glomerular injury in the animals receiving combined hormone treatment. TGF-b1 and 2. Lei J, Silbiger S, Ziyadeh FN, Neugarten J. Serum stimulated a1 PDGF-A are important mediators of tissue fibrosis in type IV collagen gene transcription is mediated by TGFb and both the glomeruli and in the tubulointerstitial space.
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replacement improves proteinuria and impaired creatinine Subtotal nephrectomy: a mosaic of growth factors. Nephrol clearance in type 2 diabetes mellitus and hypertension. BJOG Received for publication: 7.1.02Accepted in revised form: 20.8.02

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