Clinical and experimental studies indicate that the progression of renal disease is faster in males than females. These observations are corroborated by a sexual dimorphism observed in the polygenetic MWF (Munich Wistar Frömter) rat model. The age-dependent spontaneous progression of increased UAE (urinary albumin excretion) in male MWF rats is influenced by multiple QTLs (quantitative trait loci). In contrast, female MWF rats only develop a slight increase in UAE, while the role of genetic factors for this phenotype is unknown. In the present study, we show that, compared with resistant SHRs (spontaneously hypertensive rats), both male and female MWF rats develop a significant increase in UAE at 24 weeks of age (P<0.0001), although blood pressures were lower compared with SHRs (P<0.0001). UAE was significantly higher in male (7-fold) compared with female MWF rats (162.6±15.9 compared with 24.0±5.5 mg/24 h respectively; P<0.0001), and only male MWF rats developed significant glomerulosclerosis and tubulointerstitial damage in the kidney (P<0.0001). To test the role of genetic factors in the development of low grade albuminuria in female MWF rats, we analysed the role of a major UAE QTL on rat chromosome 6. To this end, we analysed a consomic MWF-6SHR strain in which chromosome 6 from SHRs was introgressed into the MWF rat background. Time course analysis of UAE in females indicated that the small increase in UAE in MWF rats was fully suppressed by exchange of rat chromosome 6. Thus, taken together with previous studies in males, we show that RNO6 protects against the increase in albuminuria with age in both female and male MWF rats.

INTRODUCTION

Currently, it is becoming increasingly evident that the development, manifestation and progression of cardiovascular and renal diseases differ between women and men [1]. With regard to renal disease, a large body of evidence obtained in various animal models has indicated that the progression of renal injury and failure is more pronounced in males compared with females [1,2]. A previous meta-analysis involving 11345 patients with non-diabetic renal disease confirmed these experimental observations by showing that progression of chronic renal disease is slower in female than in male patients [3]. However, another meta-analysis enrolling a significantly smaller number of only 1860 patients suggested that the rate of renal disease progression may be even faster in women compared with men if the analysis accounted for other factors that are associated with a faster rate of progression [4]. In diabetic nephropathy, i.e. the major single cause of end-stage renal disease, it remains unclear whether gender status affects the progression of the disease [1,5,6].

In addition to gender, experimental and clinical studies carried out in the last decade have documented a role for genetic factors contributing to the development of both diabetic and non-diabetic renal disease [7,8]. An increase in UAE (urinary albumin excretion) is an important predictor for the development of chronic nephropathy, and already a slight increase in UAE represents an independent risk factor for cardiovascular events and mortality not only in arterial hypertension and diabetes, but also in the general population [7,9]. Several QTLs (quantitative trait loci) have been identified by genome-wide linkage analyses for UAE in patients with diabetes or hypertension and in the general population [1012] and in several hypertensive genetic rat models [1319]. In accordance with other rat models of renal damage, the MWF (Munich Wistar Frömter) rat has a marked sexual dimorphism with regard to the progression of renal injury [1,2,20]. Thus male MWF rats exhibit spontaneous hypertension and increased UAE, leading to overt proteinuria and progressive glomerulosclerosis with age [20]. In contrast, female rats develop lower BPs (blood pressures), only mild albuminuria and are protected from glomerulosclerosis [2022]. We have therefore focussed in our previous genetic studies, aiming to dissect the genetic basis of UAE in the MWF rat strain, only on male animals [7,17,18]. We have demonstrated recently that, although albuminuria in male MWF rats is determined by a complex interplay of several QTLs, genetic exchange of one major locus on rat chromosome 6 (RNO6) leads to marked suppression of early onset albuminuria and subsequent renal damage in male animals [7]. This was achieved by targeted breeding and characterization of consomic MWF-6SHR rats in which RNO6 from albuminuria-resistant SHRs (spontaneously hypertensive rats) [16,23] was introgressed into the isogenic background of MWF rats. However, the relevance of genetic factors in the modulation of mild albuminuria observed in female MWF rats has not been studied to date. We therefore investigated whether genetic factors, i.e. a QTL on RNO6, are also capable of modulating low-grade albuminuria in female MWF rats that are protected from overt renal disease by their gender status.

MATERIALS AND METHODS

Animals and experimental groups

All animals from MWF/Rkb, SHR/Rkb and our recently generated consomic MWF-6SHR strain [7] were obtained from our colonies (laboratory code Rkb) at Charité-Universitätsmedizin Berlin, Berlin, Germany. The consomic strain MWF-6SHR was derived from MWF/Rkb and SHR/Rkb, and was generated by sequential marker-assisted backcrossing transferring the whole RNO6 from SHRs into the MWF rat background, as described previously [7]. Rats were grouped under conditions of regular 12 h diurnal cycles using an automated light-switching device and climate-controlled conditions at a room temperature of 22 °C. The rats were fed a normal diet containing 0.2% NaCl and had free access to food and water.

Study A

In study A, we evaluated first the sexual dimorphism in adult SHRs and MWF rats at 24 weeks of age. For this, male and female SHRs (n=10 of each) and MWF rats (n=18–19 of each) were selected, SBP (systolic BP) and UAE were measured and renal histology analysis was performed by determination of glomerulosclerosis and tubulointerstitial damage indices.

Study B

The aim of study B was to evaluate the role of RNO6 in the development of albuminuria and renal damage in female MWF rats. We therefore compared female consomic MWF-6SHR rats (n=20) with female MWF rats (n=18) and female SHRs (n=10) with low UAE. In these animals, in accordance with previous studies [7,17,18], time-course analysis of UAE at 8, 14, 18 and 24 weeks of age was performed. In addition, body and organ weights of the heart and kidney, plasma concentrations of creatinine and urea, creatinine clearance, renal structural changes and renal collagen III mRNA expression were determined.

Animals in study A and B were killed after measuring UAE and SBP at 24 weeks of age.

Study C

As male MWF rats develop progressive overt albuminuria with age, a subgroup of female MWF and consomic MWF-6SHR rats (n=8 of each) from study B were followed to investigate the development of UAE in older female animals at 32 weeks of age. The results were compared with the findings obtained in age-matched male animals analysed in a recent study [7].

Laboratory measurements

For urine analysis, animals were placed in metabolic cages for 2 days. The first day was used for adaptation, and urine was collected for the last 24 h for biochemical analysis. UAE as an indicator of renal damage was measured by a rat-specific ELISA, as described previously [22].

SBP was measured at 24 weeks of age by a non-invasive tail-cuff method in awake animals using a computer-assisted oscillatory detection device (TSE), as described previously [22]. These measurements involved two training sessions on 2 days, followed by up to 18 (minimum 12) recordings in awake rats on three consecutive days, as reported previously [22]. Blood was drawn from the aorta for the determination of serum creatinine and urea using standard methods. Both kidneys and the heart were excised. The body, total kidney and heart weights were determined. For light microscopy evaluation, the left kidney was fixed and embedded in paraffin for histology studies, including determination of GSI (glomerulosclerosis index), TDI (tubulointerstitial damage index) and quantification of RIF (renal interstitial fibrosis), as described previously [17].

RNA analysis

RNA was isolated from kidneys by the TRIzol® reagent (Invitrogen), according to the manufacturer's instructions, and was resuspended in DEPC (diethyl pyrocarbonate)-treated water. First-strand cDNA synthesis was carried out on 2 μg of total RNA in a 20 μl reaction using the First Strand cDNA Synthesis Kit (Fermentas Life Sciences), following the manufacturer's recommendations. To quantify mRNA expression of collagen III in kidney, we employed a real-time quantitative reverse transcriptase (TaqMan) PCR method, as reported previously [7]. To normalize our expression data, PBGD (porphobilinogen deaminase) was used as a housekeeping gene (GenBank® accession no. X06827), as reported previously [7].

Statistical analysis

Statistical analysis was performed using two-way ANOVA, followed by Bonferroni's adjustment, and by a non-parametric Mann-Whitney U test. Values are means±S.E.M., and P values <0.05 were considered significant.

RESULTS

Study A: evaluation of sexual dimorphism in adult SHRs and MWF rats

At the age of 24 weeks, SBPs were significantly lower in both adult male and female parental MWF rats compared with male and female SHR rats (P<0.0001; Figure 1A). A sexual dimorphism with higher SBP in males compared with females (P<0.01) was observed in SHR, whereas the BP difference in MWF animals, with somewhat lower values in females, were not significant. In contrast with BPs, UAE was overall markedly elevated in MWF rats compared with SHRs (P<0.0001; Figure 1B). Both male and female SHRs had comparably low UAE of approx. 2 mg/24 h, whereas MWF rats had a striking sexual dimorphism, with approx. 7-fold higher values in male (162.6±15.9 mg/24 h) compared with female (24.0±5.5 mg/24 h) animals (Figure 1B; P=0.0003). Analysis of structural changes in the kidney of these animals at 24 weeks of age demonstrated a significant increase in GSI and TDI, i.e. glomerular and tubulointerstitial damage, in male MWF rats compared with female MWF rats and SHRs of both sexes (P<0.0001; Figure 2). Representative images of the histology performed after PAS (periodate–Schiff) staining are shown in Figure 3.

SBP (A) and UAE (B) in female (open bars) and male (solid bars) SHRs and MWF rats at 24 weeks of age

Figure 1
SBP (A) and UAE (B) in female (open bars) and male (solid bars) SHRs and MWF rats at 24 weeks of age

*P<0.0001 compared with SHRs of the same gender; #P<0.01 compared with males of the same strain.

Figure 1
SBP (A) and UAE (B) in female (open bars) and male (solid bars) SHRs and MWF rats at 24 weeks of age

*P<0.0001 compared with SHRs of the same gender; #P<0.01 compared with males of the same strain.

GSI (A) and TDI (B) in female (open bars) and male (solid bars) SHRs and MWF rats at 24 weeks of age

Figure 2
GSI (A) and TDI (B) in female (open bars) and male (solid bars) SHRs and MWF rats at 24 weeks of age

*P<0.0001 compared with the other groups.

Figure 2
GSI (A) and TDI (B) in female (open bars) and male (solid bars) SHRs and MWF rats at 24 weeks of age

*P<0.0001 compared with the other groups.

Histopathology of the kidney in the rat strains at 24 weeks of age

Figure 3
Histopathology of the kidney in the rat strains at 24 weeks of age

Paraffin sections were stained with PAS reagent. Representative images from a female SHR (A), MWF rat (B) and consomic MWF-6SHR rat (C) are shown. (D–F) Corresponding male animals. No female animals (A–C) or male SHRs (D) had severe abnormalities. In contrast, male MWF rats (E) had significant glomerulosclerosis in two glomeruli, tubulointerstitial infiltration and tubular casts, whereas male consomic MWF-6SHR rats (F) had intermediate glomerulosclerosis.

Figure 3
Histopathology of the kidney in the rat strains at 24 weeks of age

Paraffin sections were stained with PAS reagent. Representative images from a female SHR (A), MWF rat (B) and consomic MWF-6SHR rat (C) are shown. (D–F) Corresponding male animals. No female animals (A–C) or male SHRs (D) had severe abnormalities. In contrast, male MWF rats (E) had significant glomerulosclerosis in two glomeruli, tubulointerstitial infiltration and tubular casts, whereas male consomic MWF-6SHR rats (F) had intermediate glomerulosclerosis.

Study B: evaluation of the role of rat chromosome 6 in female consomic MWF-6SHR rats

Time-course analysis for UAE between weeks 8 and 24 in female consomic MWF-6SHR rats compared with parental MWF rat and SHR strains is shown in Figure 4. In contrast with SHRs, female MWF rats already had a significant increase in UAE at 8 weeks of age (0.1±0.01 compared with 5.2±0.8 mg/24 h respectively; P<0.0001; Figure 4). UAE progressed with age in female MWF rats, with mean values of 24.0 mg/24 h at 24 weeks. This increase was fully suppressed in female consomic animals at all of the time points investigated (P<0.0001; Figure 4); only a slight increase was seen, with values up to 1.7 mg/24 h at 24 weeks of age. Overall, no significant differences in UAE between female consomic MWF-6SHR rats and female SHRs was observed. At 24 weeks of age, ANOVA revealed no significant differences in body and kidney weights between the female rats of the three strains (Table 1). Determination of SBP in consomic rats demonstrated values similar to female MWF rats, thus SBP was lower in both strains compared with SHRs (P<0.0001; Table 1). Replacement of RNO6 in the consomic strain resulted in lower serum urea concentrations compared with female parental MWF rats (P<0.0001; Table 1), whereas heart weight, serum creatinine and creatinine clearance at 24 weeks of age were not affected, as summarized in Table 1. In addition, as expected from the results obtained in the kidney histology analysis in female parental MWF rats and SHRs, GSI and TDI were also lower in female MWF-6SHR rats and not significantly different from female rats of the other two strains (results not shown). However, the quantitative analysis of RIF in female MWF rats revealed a significant, albeit slight, increase in fibrosis compared with SHRs (P=0.04), whereas consomic animals had intermediate levels (Table 1). In addition, collagen III mRNA expression was significantly increased in female MWF rats compared with SHRs (P=0.0002), whereas consomic animals had significantly lower expression levels compared with MWF rats (P=0.04) and were not statistically different from SHRs (Table 1).

Time course analysis of UAE in female SHRs (white bars), consomic MWF-6SHR rats (grey bars) and MWF rats (black bars) at 8, 14, 18 and 24 weeks of age

Figure 4
Time course analysis of UAE in female SHRs (white bars), consomic MWF-6SHR rats (grey bars) and MWF rats (black bars) at 8, 14, 18 and 24 weeks of age

*P<0.0001 compared with SHRs and MWF-6SHR rats respectively.

Figure 4
Time course analysis of UAE in female SHRs (white bars), consomic MWF-6SHR rats (grey bars) and MWF rats (black bars) at 8, 14, 18 and 24 weeks of age

*P<0.0001 compared with SHRs and MWF-6SHR rats respectively.

Table 1
Overall characteristics of female parental MWF rats, SHRs and consomic MWF-6SHR rats at 24 weeks of age

Crea Cl, creatinine clearance; PBGD, porphobilinogen deaminase.

GroupP value from ANOVA
CharacteristicSHRsMWF-6SHR ratsMWF ratsOverallMWF×SHRMWF×MWF-6SHRSHR×MWF-6SHR
Body weight (g) 208.0±5.5 214.4±5.2 207.2±1.2 0.4 − − − 
SBP (mmHg) 157.1±2.9 139.0±1.6 138.5±1.2 <0.0001 <0.0001 1.0 <0.0001 
Kidney weight (g) 1.28±0.05 1.30±0.05 1.20±0.03 0.07 − − − 
Kidney weight/body weight (g) 6.15±0.16 6.06±0.16 5.78±0.13 0.09 − − − 
Heart weight (g) 0.76±0.03 0.66±0.03 0.62±0.01 <0.0001 <0.001 1.0 0.02 
Heart weight/body weight (mg/g) 3.67±0.10 3.08±0.10 2.98±0.02 <0.0001 <0.0001 1.0 <0.0001 
Serum creatinine (μmol/l) 35.5±1.6 42.3±1.1 41.9±0.4 <0.001 <0.01 1.0 0.002 
Serum urea (mmol/l) 6.83±0.24 6.88±0.24 9.32±0.39 <0.0001 <0.0001 <0.0001 1.0 
Crea Cl (ml·min−1·100 g−10.47±0.05 0.37±0.04 0.38±0.02 0.02 0.56 1.0 0.45 
Renal interstitial fibrosis (%) 4.0±0.2 4.5±0.1 4.9±0.3 0.05 0.04 0.92 0.35 
Collagen III/PBGD (ratio) 1.8±0.2 2.9±0.3 4.5±0.7 0.0003 0.0002 0.04 0.16 
GroupP value from ANOVA
CharacteristicSHRsMWF-6SHR ratsMWF ratsOverallMWF×SHRMWF×MWF-6SHRSHR×MWF-6SHR
Body weight (g) 208.0±5.5 214.4±5.2 207.2±1.2 0.4 − − − 
SBP (mmHg) 157.1±2.9 139.0±1.6 138.5±1.2 <0.0001 <0.0001 1.0 <0.0001 
Kidney weight (g) 1.28±0.05 1.30±0.05 1.20±0.03 0.07 − − − 
Kidney weight/body weight (g) 6.15±0.16 6.06±0.16 5.78±0.13 0.09 − − − 
Heart weight (g) 0.76±0.03 0.66±0.03 0.62±0.01 <0.0001 <0.001 1.0 0.02 
Heart weight/body weight (mg/g) 3.67±0.10 3.08±0.10 2.98±0.02 <0.0001 <0.0001 1.0 <0.0001 
Serum creatinine (μmol/l) 35.5±1.6 42.3±1.1 41.9±0.4 <0.001 <0.01 1.0 0.002 
Serum urea (mmol/l) 6.83±0.24 6.88±0.24 9.32±0.39 <0.0001 <0.0001 <0.0001 1.0 
Crea Cl (ml·min−1·100 g−10.47±0.05 0.37±0.04 0.38±0.02 0.02 0.56 1.0 0.45 
Renal interstitial fibrosis (%) 4.0±0.2 4.5±0.1 4.9±0.3 0.05 0.04 0.92 0.35 
Collagen III/PBGD (ratio) 1.8±0.2 2.9±0.3 4.5±0.7 0.0003 0.0002 0.04 0.16 

Study C: role of rat chromosome 6 in aging female MWF rats compared with male MWF rats

In contrast with old male animals, which develop according to our previous analysis mean UAE levels of up to approx. 355 mg/24 h (range, 206–561 mg/24 h) [7], female MWF rats only had UAE of 18.6±3.0 mg/24 h at 32 weeks of age. The latter values were comparable with the UAE observed in female MWF rats at 24 weeks of age (Figure 4). Thus female MWF rats have no significant progression of UAE between weeks 24 and 32. Despite the striking sexual dimorphism in absolute amounts of UAE between male and female MWF rats, the relative suppression of UAE conferred by the transfer of RNO6 in consomic MWF-6SHR animals appears similar in males and females, as summarized in Figure 5 (approx. 85–95% reduction compared with parental MWF rats of the same sex).

UAE in male and female consomic MWF-6SHR rats (grey bars) and MWF rats (black bars) at 32 weeks of age

Figure 5
UAE in male and female consomic MWF-6SHR rats (grey bars) and MWF rats (black bars) at 32 weeks of age

*P<0.0001 compared with consomic animals. The numbers given indicate the percentage of UAE in relation to the parental MWF strain.

Figure 5
UAE in male and female consomic MWF-6SHR rats (grey bars) and MWF rats (black bars) at 32 weeks of age

*P<0.0001 compared with consomic animals. The numbers given indicate the percentage of UAE in relation to the parental MWF strain.

DISCUSSION

The MWF rat represents a valuable model for studying the mechanisms involved in progressive glomerular injury and renal failure [24]. This inbred rat strain develops mild arterial hypertension, albuminuria and glomerulosclerosis, and has a reduction in nephron number [7,20]. In the present study, we investigated the role of a previously identified important albuminuria QTL on RNO6 [18] for the development of albuminuria in female rats, which have, in contrast with male rats, only low-grade albuminuria. Our time-course analysis of UAE in female consomic MWF-6SHR rats demonstrated that the small increase in UAE observed in female MWF rats was fully suppressed by the exchange of rat chromosome 6. Taken together with previous studies in males [7], we show that RNO6 protects against the increase in albuminuria with age in both female and male MWF rats.

The sexual dimorphism of renal disease phenotypes observed in this model reflects clinical findings in non-diabetic renal disease, indicating that disease progression is lower in females than in males [13,5]; however, the biological basis for this phenomenon is not fully understood. In MWF animals, both females and males share the same reduction in nephron number, as demonstrated by Fassi et al. [20]. Thus the lower UAE and protection from overt proteinuria and structural damage of the kidney in female MWF rats are probably not attributable to differences in nephron development. Our previous studies in male MWF animals indicated that the increased UAE in MWF rats is a polygenetic trait that is influenced by up to 11 UAE QTLs that are not linked to BP [17,18]. Although the genetic studies in male MWF rats indicated that the increase in UAE is independent of BP, the possibility that the somewhat lower BPs observed in female MWF rats are contributing to the lower UAE in female animals could not be excluded.

On the other hand, it appears possible that gender-specific QTL effects [25] may explain, in part, the sexual dimorphism of UAE in the MWF strain. However, this question has not been addressed in previous QTL mapping studies, which included only male MWF animals because of their more pronounced phenotypes [17,18]. Similarly, QTL mapping studies for UAE phenotypes in the Dahl salt-sensitive rat were also restricted to male animals and led to the identification of multiple QTLs in male rats only [15,16]. However, in a subsequent study by Garrett et al. [26], the confirmation of UAE QTLs in congenic strains derived from Dahl salt-sensitive rats was reported to be similar in male and female animals, although no results for female rats were shown.

As a result of the studies in male MWF rats, we recently confirmed an important role of RNO6 in albuminuria development in male animals [7]. In the present study, we show for the first time that genetic factors, i.e. a QTL on RNO6, also influence the development of albuminuria in female MWF rats. Thus transfer of RNO6 from SHRs in the MWF background is protective in both sexes.

Comparative mapping analysis [27] between the 99% and 95% confidence intervals for placement of the albuminuria QTL on RNO6 with the human genome maps this region to human chromosome 14q23.1–14q31.3. This region contains 146 annotated genes. Currently, we are not able to give any indication which gene(s) within the RNO6 region is (are) responsible for onset of albuminuria in MWF rats; however, the findings in both female and male MWF-6SHR rats validate this region and provide the rationale to develop further congenic rats carrying smaller intervals, thereby reducing the number of genes within the QTL for further investigation.

It has already been shown that morphological changes in the glomerular basement membrane or ultrastructure of the podocytes are not responsible for the development of albuminuria in the MWF model [28]. More recent findings have demonstrated that progressive proteinuria in male animals is associated with damage and loss of podocytes [24]. As renal damage is only mild in female compared with male MWF animals, no major differences in renal function and renal structural damage were detected in consomic animals as expected, except that serum urea and renal collagen III expression were significantly reduced compared with parental MWF animals.

Previously, Fassi et al. [20] provided evidence for glomerular hyperfiltration in MWF animals by showing a 2-fold increase in single nephron glomerular filtration rate in this strain. In addition, they demonstrated that, in comparison with normal Wistar rats, both male and female MWF animals had a similar approx. 50% reduction in total glomeruli number [20]. Consequently, in the latter study, total glomerular filtration rate was not significantly different between sex-matched MWF and Wistar rats at an early adult age of 12–14 weeks. The results obtained in the present study indicate that renal function, as determined by serum creatinine concentrations and creatinine-clearance, was impaired in female MWF and consomic MWF-6SHR rats compared with SHRs at 24 weeks of age. It is well-established that renal function progressively declines in aging male MWF rats with progressive proteinuria, probably due to severe structural damage [7,29]. Although our present results would suggest that overall glomerular filtration rate is also lower in older female MWF rats compared with SHRs, it appears possible that single glomeruli of female MWF rats are hyperfiltrating, as we have shown recently that the total number of glomeruli in the MWF strain is also significantly reduced (approx. −30%) when compared with the SHR strain [7]. On the other hand, our findings document that the lower creatinine clearance in MWF and consomic animals cannot be related to differences in albuminuria, which was similar between consomic animals and SHRs, or to differences in renal structural damage, which was low and similar in females of all three strains. To obtain further insights into the renal function of female MWF and consomic animals would require additional studies investigating renal and glomerular haemodynamics in relation to the total number of glomeruli in these animals and in comparison with female SHRs using appropriate methods, e.g. inulin-clearance measurements for the determination of glomerular filtration rate [20]. SBPs were similar in female MWF and consomic animals, thus clearly ruling out a role of BP differences as an explanation for the suppressed albuminuria in MWF-6SHR rats.

It is well-established that aging male animals of some strains of rats develop spontaneous proteinuria and glomerulosclerosis, whereas treatment with oestrogens or orchiectomy protects against renal damage in older age [2]. In addition, investigations in various renal disease models indicated that progression of renal injury can be modulated by surgical or pharmacological change in the sex hormonal status in both male and female rats [2]. These findings support the overall concept that androgens are deleterious and oestrogens are protective for renal disease progression in experimental models. Moreover, gender-specific differences of important factors regulating renal function, such as the renin–angiotensin system [1,30,31] and renal NOS (NO synthase) isoforms [32,33], have been implicated in the sexual dimorphism of renal disease progression. Previous studies performed in Munich Wistar rats, i.e. the genetic background of MWF animals, indicated that the presence of androgens in male rats, rather than the absence of oestrogens, provide the risk factor for the development of age-dependent proteinuria and glomerular damage in this strain [34]. The present study demonstrates that early onset of albuminuria at 8 weeks of age in female MWF rats is comparable with the early increase of UAE in male rats [7]. Subsequently, female rats develop only a slight increase in UAE after maturation, reaching a plateau between weeks 24 and 32, whereas males have a marked progression with age. The similar suppression of albuminuria in female and male rats induced by exchange of the RNO6 QTL supports the conclusion that the same genetic mechanisms are responsible for the onset of albuminuria in both male and female MWF rats, whereas sexual dimorphism is probably attributable to non-genetic factors, such as the influence of sex hormones. Future studies should aim to characterize how changes in sex hormonal status affect the genotype–phenotype affects in albuminuria.

Abbreviations

     
  • BP

    blood pressure

  •  
  • GSI

    glomerulosclerosis index

  •  
  • MWF rat

    Munich Wistar Frömter rat

  •  
  • PAS

    periodate–Schiff

  •  
  • QTL

    quantitative trait locus

  •  
  • RIF

    renal interstitial fibrosis

  •  
  • SBP

    systolic BP

  •  
  • SHR

    spontaneously hypertensive rat

  •  
  • TDI

    tubulointerstitial damage index

  •  
  • UAE

    urinary albumin excretion

We acknowledge the contributions of Sabine Wunderlich and Claudia Plum for laboratory assistance, and Bettina Bublath for support in animal breeding. This study was supported by grants from the DFG (Deutsche Forschungsgemeinschaft) KR1152-3-1.

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