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Endocrinology Vol. 141, No. 3 932-937
Copyright © 2000 by The Endocrine Society

ARTICLES

Early Hyperplastic Renal Growth after Uninephrectomy in Adult Female Rats1

Susan E. Mulroney and Carlo Pesce

Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, D.C. 20007; and DISTBIMO, Center for Anatomical Pathology, University of Genova (C.P.), Genova, Italy

Address all correspondence and requests for reprints to: Susan E. Mulroney, Ph.D., Department of Physiology and Biophysics, Georgetown University School of Medicine, 3900 Reservoir Road NW, Washington, D.C. 20007. E-mail: mulrones{at}gusun.georgetown.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The early, accelerated remnant kidney growth following uninephrectomy (UNX) occurs through alternate mechanisms in juvenile and adult male rats, which may govern the type of renal growth that occurs after UNX. Early compensatory renal growth (CRG) in the adult male rat is GH dependent, but independent of changes in the renal insulin-like growth factor I (IGF-I) system. In contrast, CRG is GH independent in the juvenile male rat, but is associated with significant increases in the renal IGF-I system, and hyperplastic kidney growth. The few studies that examined early CRG in female animals suggest that remnant kidney growth is less than that observed in males, and there is a hyperplastic component, indicating potential gender differences. Whether these differences result from alternate growth mechanisms is unknown. The purpose of the present study was to determine the rate, type, and potential mechanism of early remnant kidney growth in adult female rats after UNX. GH levels were determined in conscious, sham-operated, and UNX adult female Wistar rats 24 h postsurgery. Unlike previous findings in adult male UNX rats, pulsatile GH levels were not elevated in UNX female rats. When GH release was suppressed using an antagonist to GH-releasing factor, remnant kidney growth was not different from that in saline/UNX remnant kidneys (25.7 ± 4.8% vs. 27.7 ± 2.1%, respectively, at 48 h post-UNX). This GH-independent CRG was associated with significant hyperplastic growth in both adult and juvenile female remnant kidneys, as determined by bromodeoxyuridine incorporation and increases in total DNA. Also associated with the mitogenic growth in the adult female were significant 2- to 4-fold increases in remnant kidney IGF-I receptor gene expression, which occurred in the presence and absence of pulsatile GH secretion. Lastly, the growth rate of adult female remnant kidneys was not different from that observed in male remnant kidneys at these early time points (0.21 ± 0.02 vs. 0.20 ± 0.02 g at 24 h, and 0.26 ± 0.02 vs. 0.30 ± 0.03 g at 48 h in female and male remnant kidneys, respectively; P = NS). Thus, in female rats, the initial phase of CRG is GH independent, but is associated with significant increases in remnant kidney IGF-I receptor gene expression and hyperplastic renal growth. This, in addition to previous findings, indicates that there are sex differences in early CRG after UNX. Moreover, the findings confirm that the mechanism governing the initial phase of CRG appears to be a critical determinant for significant hyperplastic remnant kidney growth.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
RECENT STUDIES have determined that there are age-related differences in the initial phase of compensatory renal growth (CRG) following uninephrectomy (UNX) in male rats. In adult male rats, circulating GH levels (24–48 h post-UNX) are elevated 3- to 4-fold compared with those in sham-operated animals. When this increase in GH is blocked using an antagonist to GH-releasing factor (GRF-AN; [N-Ac-Tyr1,Arg2]-GRF-(1–29)-NH2), remnant kidney growth is significantly attenuated (1). Interestingly, this GH-dependent CRG occurs without increases in remnant kidney insulin-like growth factor I (IGF-I) messenger RNA (mRNA) (2, 3) or protein (3), and is hypertropic in nature (4). In contrast to that observed in the adult male, CRG in juvenile male rats is GH independent, is associated with significant increases in IGF-I gene expression, and displays a significant hyperplastic component (4, 5). The differential mechanisms initiating CRG in the pre- and postpubertal male animals support the concept that gonadal steroids may play a role in the type of CRG that occurs with age. If this is true, there may also be early differences in CRG between the sexes.

Although in previous studies female UNX animals were primarily used as controls for male CRG, there were indications of gender differences in the early UNX paradigm. Studies in rodents (6, 7, 8) determined that the CRG response (within ~7 days) was less in female animals than in their male counterparts. Furthermore, several reports observed hyperplastic growth in the female, but not male, remnant kidneys (9, 10). These reports did not elaborate on the differences in growth patterns between the sexes, except to comment that perhaps testosterone was a driving force for the greater growth in the male animals compared with female remnant kidneys. Early studies in castrated male rats suggested that testosterone was a renal growth factor, and kidneys actually regressed in weight when testosterone was removed (6). These studies, however, were not performed under optimal conditions, as UNX was performed at the same time as castration. It is now known that it takes 8–10 days for endogenous testosterone to be cleared from the castrated animals, so findings using the earlier experimental design cannot be properly interpreted. A single, more recent study performed UNX after castration and was able to implicate testosterone in the early CRG response (7).

In summary, there is evidence indicating differences in remnant kidney growth in the early phase of CRG; however, none of the reports has clearly examined the mechanisms or gender differences. The finding of hyperplastic renal growth in female UNX rodents supports the concept that CRG in the female may be more similar to that observed in the hyperplastic, IGF-I-associated remnant kidney growth in the juvenile male animal (4) and, therefore, may have an initial mechanism different from that in adult males. The purpose of the present study was to determine the rate, type, and potential mechanism governing the initial phase of CRG in the adult female rat.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
GH secretion after UNX in female rats
All procedures were performed in accordance with guidelines approved by the university animal care and use committee. Adult female Wistar rats (12–14 weeks of age) were anesthetized with ether, and SILASTIC brand catheters (Dow Corning Corp., Midland, MI) were placed in their right jugular veins for blood sampling. An incision was made in the left flank, and the kidney was decapsulated (adrenal gland remained intact), ligated with 4–0 silk suture, and excised. The area was cleansed with antimicrobial agent Amerse (ConvaTec, St. Louis, MO), and the flank incision was sutured closed. The animals were allowed to recover for 24 h. Body and kidney weights were measured. The control, excised kidneys were flash-frozen for biochemical and molecular studies. Sham-operated animals were catheterized, and a left flank incision was made: the kidneys were manipulated, and the incision was closed. Beginning 24 h post-UNX (n = 9) or sham operation (n = 8), sequential blood samples (0.2 ml) were taken in heparinized syringes every 20 min over a 6-h period in the conscious, unrestrained animals, as previously described (1, 5). Plasma was extracted from each sample and stored at -70 C until GH was measured by RIA. Packed blood cells were resuspended in saline and injected into the rats to minimize blood losses over the experimental period. When the experiment was concluded, animals were weighed and killed, and remnant or sham-operated kidneys were removed, weighed, and flash-frozen. Separate groups of adult male rats underwent left UNX, and remnant kidney growth at 24 and 48 h was compared with that in the female rat.

Time course for remnant kidney growth in adult female rats
To assess the rapid remnant kidney growth response in the adult female, animals underwent left nephrectomy, and remnant kidneys were excised at 1, 18, 24, 48, and 72 h post-UNX in separate groups of animals. Body and kidney weights were determined.

Determination of mitogenic renal growth
To confirm our hypothesis that early CRG in the female rat was associated with a significant mitogenic, hyperplastic component, separate groups of juvenile (4 weeks old) and adult (12 to 14 weeks old) females rats underwent UNX or sham operation, and 23 h later bromodeoxyuridine (BrdU; 12 mg/ml saline; Zymed Laboratories, Inc., San Franscisco, CA) was injected (40 mg/kg BW, ip). One hour later, animals were killed, and remnant and sham control kidneys were excised and weighed. The kidneys were sliced longitudinally and fixed in 10% formalin for BrdU studies. BrdU incorporation was compared between remnant and sham-operated kidneys in the juvenile and adult female rats. In the adult female rats, half of each sham and remnant kidney was frozen for DNA analysis as an additional confirmation of mitogenesis.

Effect of GH suppression on remnant kidney weight gain in female rats
To determine whether pulsatile GH drives early CRG in the adult female rat, adult female animals were instrumented with jugular catheters and underwent left UNX. Beginning immediately after UNX, animals were injected iv twice daily (at 0830 and 1330 h) with either saline vehicle (0.1 ml; n = 6) or GRF-AN (100 µg/kg in 0.1 ml; Bachem, Torrance, CA). We previously reported that this dosage regimen of the antagonist is effective in suppressing pulsatile GH release (1, 11). The catheters were maintained patent with 0.1 ml sodium heparin (250 U/ml) after each injection. Body weights and excised kidney weights were obtained at the onset of the experiment (kidneys frozen), and animals were allowed food and water ad libitum. After 24 (n = 9) or 48 (n = 6) h of treatment, animals were weighed and killed, and remnant kidneys were excised, weighed, flash-frozen, and stored at -70 C until assay. A separate group of male rats underwent UNX in the presence (n = 3) or absence (n = 3) of GRF-AN to serve as controls for GH-dependent remnant kidney growth, as previously reported (1).

Solution hybridization/ribonuclease (RNase) protection assay
IGF-I receptor mRNA in control (left, excised) and remnant (compensated) kidneys was determined by solution hybridization/RNase protection assay. We previously determined that the IGF-I receptor message is associated with early hyperplastic CRG in juvenile male rats (4), but not with hypertropic remnant kidney growth in adult male rats (2, 3). Tissue samples (~0.2 mg) were homogenized (Tekmar, Cincinnati, OH), and total RNA was extracted from kidney tissue using the guanidinium-isothiocyanate/cesium chloride technique (2, 3, 4). The RNA was quantified spectrophotometrically by the absorbance at 260 nm, and the integrity of the RNA was confirmed by comparing the ethidium bromide-stained 18S and 28S ribosomal RNA bands. RNase protection assays were performed as previously described (3, 4). Briefly, in separate experiments, 20-µg samples of total RNA were hybridized with a 32P-labeled homologous antisense probe to the IGF-I receptor. The probe to the IGF-I receptor mRNA is a 305-bp construct that yields a protected band of 265 bp (3, 4). After hybridization, RNA samples were digested with RNases A and T1, and the hybrids were extracted with phenol-chloroform, precipitated with ethanol, and electrophoresed on an 8% polyacrylamide-8 M urea denaturing gel. Each sample was analyzed on multiple gels, and several autoradiographic exposures were obtained and quantified by computerized scanning densitometry or phosphorimaging. The level of mRNA in the remnant kidney was compared with that in the excised control kidney from each animal, and statistical comparison was determined by paired Student’s t tests.

GH RIA
Plasma GH levels were determined using a kit provided by the NIDDK Hormone and Pituitary Program, as previously described (1, 5). The sensitivity of the assay is 0.26 ng/ml, with intra- and interassay coefficients of variability of less than 7%. Samples were measured in duplicate within the same assay. Measurements of each time point were averaged (mean ± SEM) for the different groups, and statistical comparison between groups was made using unpaired Student’s t tests. The integrated area under the curve for GH profiles was determined using KaleidaGraph software for the Macintosh computer. The means of individual integrated areas were compared between groups by unpaired Student’s t tests.

DNA and protein determination
Control and remnant kidney total DNA was determined by the method of Burton (12). Protein concentrations were determined using reagents from Bio-Rad Laboratories, Inc. (Hercules, CA).

BrdU immunocytochemistry
Formalin-fixed kidney tissues were embedded in paraffin blocks, and 5-µm slices were placed on glass slides. Immunohistochemical staining was performed using a kit and protocol obtained from Zymed Laboratories, Inc.

Statistical analysis
Comparisons of each individual animal’s control and remnant kidneys was performed using paired Student’s t tests. Comparisons between different groups used unpaired Student’s t tests. Significance was designated at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
GH secretion after UNX in female rats
Figure 1Go illustrates pulsatile GH release in sham-operated and UNX female rats over a 6-h period beginning 24 h postsurgery through 30 h. GH levels in sham-operated animals are designated by the solid line. The pulses in females were erratic and of low amplitude, which has been ascribed to the effects of estrogen on GH release (13, 14). GH secretion was not dramatically altered by UNX (dotted line). Average highest peak values for the UNX animals were not significantly different from control values (32.1 ± 4.0 vs. 41.0 ± 13.7 ng/ml in UNX and control animals, respectively; P = NS). There was a small, but significant, increase in the area under the curve for GH after UNX (5784 ± 168 vs. 4658 ± 370 ng GH/6 h in controls; P < 0.05), which was attributed to a slight increase in trough GH levels. This profile was very different from that previously observed in adult UNX male rats, where peak and area under the curve values were 3- to 4-fold higher than those in controls (1). During the 24-h period, the remnant kidney of the UNX female rats grew to 20.3 ± 1.4% (0.17 ± 0.01 g) of the control (excised) kidney weight (P < 0.05), whereas sham control kidneys grew only 4.3 ± 1.1% (0.04 ± 0.01 g). The time course for remnant kidney growth is illustrated in Fig. 2Go. The remnant kidneys grew at an accelerated rate over the first 48 h post-UNX, as previously observed in the juvenile and adult male animals (2, 3, 4). Despite the lack of a rise in GH secretion in the female UNX rats, remnant kidney growth at 24 h post-UNX was comparable to that observed in the adult male remnant kidneys (Fig. 3Go, upper and middle panels). Indeed, the main difference was that the female remnant kidney had a significant amount of hyperplastic growth, as determined by increases in total DNA, compared with no significant change in DNA in the adult male remnant kidney (Fig. 3Go, lower panel). The increase in remnant KW 48 h post-UNX in the female (27.7 ± 2.1%; 0.26 ± 0.02 g) was associated with a further increase in total DNA (to 17.3 ± 1.2%).



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  		Figure 1. Plasma profiles of GH release in conscious female rats 24 h post-UNX (n = 9; dotted line) or sham operation (n = 8; solid line).

 


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  		Figure 2. Early time course for remnant kidney growth after UNX in adult female rats. The majority of the accelerated growth occurs over the initial 48 h post-UNX. * , P < 0.05 vs. 24 h control (not shown).

 


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  		Figure 3. Remnant kidney growth parameter in adult male and female rats 24 h post-UNX. Although the relative renal growth and increase in total protein were comparable between the sexes (upper and middle panels), the female displayed significant hyperplastic remnant kidney growth, as shown by increases in total DNA (lower panel). *, P < 0.05 vs. male remnant kidney.

 
To confirm that the increase in total DNA in the female remnant kidney did indeed reflect hyperplastic growth, BrdU incorporation was determined in sham control and remnant kidneys from juvenile and adult female rats. Table 1Go illustrates the relative remnant kidney growth rates at 18 and 24 h post-UNX in the different aged animals. As previously observed in juvenile male rats, juvenile female remnant kidneys had a relatively greater accelerated growth than that of their adult counterparts. In addition, proportionality ratios of control and remnant kidney weight/body weight (KW/BW) indicate that there was accelerated growth in both adult and juvenile remnant kidneys. These values were significantly greater than their control KW/BW or single KW/BW ratios from sham-operated animals (Table 1Go). Also, the magnitude of the increase in remnant KW in the juvenile female animals at 18 and 24 h was not significantly different from that observed previously in juvenile male remnant kidneys (2, 3, 4). The increase in remnant kidney weight at 24 h was associated with significant increases in BrdU incorporation in both the juvenile and adult remnant kidney cortical tubules; however, there was significantly more incorporation in the juvenile kidneys (Fig. 4Go). This confirms the total DNA findings and is consistent with the concept that there is a large hyperplastic component in the prepubertal animals [both male (4) and female], whereas the response is less in the adult female and is absent in the adult male (4) at these early time points. To ensure that the accelerated remnant kidney growth and the increase in DNA in the adult female were not the results of subtle changes in basal GH secretion, pulsatile GH was blocked in the next experiments.


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  		Table 1. Renal growth parameters in adult and juvenile female kidneys

 


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  		Figure 4. Percentage of BrdU-stained cortical tubule cells, as a measure of mitogenesis, in control (Cont) and remnant (Rem) kidneys from juvenile and adult female rats. Both juvenile and adult female remnant kidneys displayed significantly enhanced BrdU staining compared with controls, although the staining was greater in the juvenile remnant kidneys.

 
Effect of GH suppression on remnant kidney weight gain in female rats
Suppression of pulsatile GH release using GRF-AN significantly attenuated remnant kidney growth in adult male rats change of 8 ± 1% and 10 ± 2% over 24 and 48 h, respectively; P < 0.05) compared with growth in saline/UNX controls (19 ± 3% and 26 ± 2% over 24 and 48 h, respectively), confirming the findings of a previous study (1). In contrast, 24- and 48-h treatment with GRF-AN did not reduce remnant kidney growth in female rats (Fig. 5Go). Indeed, remnant kidney weights were not significantly different from those in saline-treated UNX rats. Moreover, suppressing GH did not decrease total DNA accumulation in the female remnant kidneys (change in DNA, 20.2 ± 5.2% at 24 h and 25.5 ± 3.6% at 48 h; P < 0.05 vs. control kidneys). Thus, early CRG is GH independent in adult female rats and is associated with significant hyperplasia.



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  		Figure 5. Suppressing GH using the GRF-AN did not affect the compensatory renal growth response in adult female rats.

 
IGF-I receptor gene expression in the presence and absence of the GRF antagonist
There was an average 2-fold increase (P < 0.05) in IGF-I receptor mRNA expression 24 h (and 48 h) post-UNX in the remnant compared with that in control kidneys from adult female UNX rats. Furthermore, when GH was suppressed in UNX female rats, IGF-I receptor mRNA remained elevated at both time points. Figure 6Go is a representative phosphorimage of IGF-I receptor gene expression in control (C) and remnant (R) kidneys from five adult UNX female rats treated with the GRF-AN (48 h post-UNX). The remnant kidney growth was associated with significant 2- to 8-fold increases in IGF-I receptor mRNA levels compared with values in their left kidney controls despite suppression of GH (Fig. 7Go). Thus, the increase in remnant kidney IGF-I receptor mRNA was observed in the presence or absence of GH and is consistent with our previous finding that hyperplastic remnant kidney growth is associated with elevations in IGF-I receptor gene expression (2, 3, 4).



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  		Figure 6. A representative phosphorimage of IGF-I receptor (R) mRNA in remnant (R) and control (C) kidneys 48 h post-UNX in GH-suppressed female rats. P, Probe; M, mol wt marker.

 


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  		Figure 7. Average levels of IGF-I receptor mRNA in control (set at 1-fold) and remnant kidneys from saline- and GRF-AN-treated female rats 48 h post-UNX. *, P < at least 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Previous work in this laboratory has determined that there are age-related differences in the mechanisms governing initial CRG in the male rat, and they may ultimately govern whether hyperplastic regeneration takes place in the remnant kidney. The concept that the onset of pubertal hormones may alter the CRG mechanism in the male combined with previous investigators’ findings of hyperplasia in female remnant kidneys support the presence of sex differences in the early CRG mechanism. This study has extended our previous work by determining that although the initial remnant kidney growth rate in the adult female rat is comparable to that observed in the adult male, the early CRG mechanism in the adult female is GH independent and is associated with significant increases in renal IGF-I receptor gene expression. Furthermore, remnant kidney growth contains a significant hyperplastic component, although it is relatively less than that observed in the juvenile female kidney. These findings are similar to those observed in the juvenile (immature) male rat and are completely consistent with the concepts that 1) the GH/IGF-I growth axis is dissociated in CRG; 2) hyperplasic growth is associated with increases in IGF-I receptor gene expression; and 3) that gonadal steroids may play a role in the alternate CRG mechanisms observed with age in the male and between the sexes in adults.

The presence of differential mechanisms for ostensibly the same end point, renal regeneration, is intriguing. Our hypothesis revolves around the idea that the increase in testosterone during puberty in the male provides the switch that alters the mechanism from significant hyperplasia to predominant hypertrophy. It is known that circulating testosterone does regulate GH secretion, and in fact, GH levels rise from low levels in the juvenile to their highest levels during and at the end of puberty in the male animal. This suggests an important link between the two hormones and will be an important aspect of future work. However, it does not explain the dissociation of the traditional GH/IGF-I axis in this paradigm. Typically, the growth-promoting effects of GH have been thought to be mediated by the GH-stimulated release of hepatic IGF-I into the circulation and subsequent binding to end-organ receptors or by GH acting directly on an organ, stimulating tissue IGF-I. Although GH and IGF-I have been shown to act independently of each other for certain metabolic processes, such as ammoniagenesis (15), gluconeogenesis (16), and renal phosphate transport (11), they were assumed to be linked in stimulation of growth. The present findings provide further support that for certain processes, the two growth factors do act in an independent manner.

If gonadal steroids play a role in the differential growth mechanisms post-UNX, what is occurring with estrogen in the adult female? As the alternate CRG mechanism is only observed in the adult male animal, it is probable that the switch is driven by androgens. The increase in estrogens during puberty in the female animal may merely allow for continuation of the juvenile IGF-I-associated mechanism. One reason this might occur is the propensity for estrogen to be a cofactor supporting mitogenesis in sensitive tissues, such as uterus and ovaries, where estrogen augments the IGF-I-mediated effects on reproductive tissues and hormones (17, 18, 19). This is in keeping with our hypothesis that the estrogen/IGF-I environment allows for hyperplastic growth.

Also of interest is the finding that suppression of GH in the female UNX animal actually tended to stimulate greater growth and hyperplasia in the remnant kidneys. It is not clear why removing GH in the female would actually enhance the renal growth response; however, it is interesting to speculate that under normal conditions GH might be working though yet another mechanism to affect the kidney. Recent studies have determined that GH regulates angiotensin II AT1 receptor expression in the kidney, and this mechanism is important to GH-dependent CRG in the adult male, but not female, rat (20). Indeed, glomerular AT1 receptor expression is significantly increased after UNX in adult male, but not female, remnant kidneys, and suppression of GH not only attenuates renal growth in the male, but abolishes the increase in AT1 receptor expression. One important implication of these findings is that the increase in AT1 receptor expression in male remnant kidneys may significantly contribute to the renal damage that occurs several months after UNX. We have recently reported that there is significant glomerular hypertrophy and tubular damage in remnant kidneys from male, but not female, rats only 2 months post-UNX, and gonadal steroid replacement studies indicate that the damage is testosterone driven (21). There are other reports of gender differences in renal damage, but at 9 or more months post-UNX, a much longer time point (22, 23). It is clear from both the long term as well as our shorter term studies that testosterone plays an important role in the development of renal pathology in the UNX paradigm. These animal studies also appear to correlate well with findings in humans. Studies in human kidney donors and other single kidney patients report that male donors exhibit significant proteinuria (24, 25, 26, 27, 28, 29, 30, 31) and focal glomerulosclerosis (24, 31), whereas female donors have no overt proteinuria or pathology (24, 26, 27, 30, 31). It has also been suggested that single kidney male patients have an increased incidence of hypertension (24, 31). These findings reinforce the presence of sex differences in the long term outcome of uninephrectomy.

In summary, there are sex differences in the mechanism governing the initial phase of compensatory renal growth after UNX. In contrast to previous findings in the adult male rat, CRG in the adult female rat is GH independent, has a significant hyperplastic component, and is associated with significant increases in remnant kidney IGF-I receptor gene expression. This mechanism is similar to that observed in the prepubertal male rat and is consistent with the concepts that the GH/IGF-I axis is dissociated in the UNX paradigm and that the gonadal steroids may influence the mechanisms. These findings may have important implications regarding the development of renal damage after UNX.


   Footnotes
 
1 This work was supported by NSF Grant IBN 95–11677 and grants from the National Kidney Foundation of the National Capital Area (to S.E.M.) and MURST (ex-40%) and Fondi d’Ateneo, Universita di Genova (to C.P.). Back

Received June 24, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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