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Acatalasemic mice are mildly susceptible to adriamycin nephropathy and exhibit increased albuminuria and glomerulosclerosis
© Takiue et al; licensee BioMed Central Ltd. 2012
Received: 22 October 2011
Accepted: 25 March 2012
Published: 25 March 2012
Catalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of catalase deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional catalase deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model.
ADR was intravenously administered to both homozygous acatalasemic mutant mice (C3H/AnLCsbCsb) and control wild-type mice (C3H/AnLCsaCsa). The functional and morphological alterations of the kidneys, including albuminuria, renal function, podocytic, glomerular and tubulointerstitial injuries, and the activities of catalase were then compared between the two groups up to 8 weeks after disease induction. Moreover, the presence of a mutation of the toll-like receptor 4 (tlr4) gene, which was previously reported in the C3H/HeJ strain, was investigated in both groups.
The ADR-treated mice developed significant albuminuria and glomerulosclerosis, and the degree of these conditions in the ADR-treated acatalasemic mice was higher than that in the wild-type mice. ADR induced progressive renal fibrosis, renal atrophy and lipid peroxide accumulation only in the acatalasemic mice. In addition, the level of catalase activity was significantly lower in the kidneys of the acatalasemic mice than in the wild-type mice during the experimental period. The catalase activity increased after ADR injection in wild-type mice, but the acatalasemic mice did not have the ability to increase their catalase activity under oxidative stress. The C3H/AnL strain was found to be negative for the tlr4 gene mutation.
These data indicate that catalase deficiency plays an important role in the progression of renal injury in the ADR nephropathy model.
The degree of oxidative stress and the severity of subsequent tissue injury may depend on an imbalance between the excessive production of reactive oxygen species and the antioxidant defense. The antioxidants include the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which detoxify reactive oxygen species. Catalase (E.C.188.8.131.52) is a major enzyme that catalyzes the decomposition of hydrogen peroxide (H2O2) and plays a role in cellular antioxidant defense mechanisms . The main reaction of catalase is the catalytic reaction (2H2O2 → O2+ 2H2O), which is essential for the removal of excessive H2O2 and for regulating the H2O2 concentration . Catalase limits the accumulation of H2O2 generated by various oxidases in tissue, and serves as a substrate for the Fenton reaction to produce the highly injurious hydroxyl radicals. Genetic defects of catalase were first documented by Takahara  in Japanese patients who exhibited a deficiency of blood catalase enzyme activity (acatalasemia) [4, 5]. Subsequently, an acatalasemic mouse strain (Csb) was established by Feinstein, Suter, and Jaroslow  from the progeny of x-ray-irradiated mice.
Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome in both children and adults [7, 8]. The clinicopathological syndrome may be classified as primary, secondary or familial. The primary defect in FSGS lies in the filtration barrier of the glomeruli. Disruption of the filtration barrier results in the loss of permselectivity, and macromolecules such as albumin are allowed to enter the urine. Chen et al.  reported that BALB/c mice were susceptible to renal toxicity arising from the administration of the anthracycline antibiotic, adriamycin (ADR), with selective injury to podocytes resulting in severe proteinuria and progressive renal failure [9, 10]. This was described as the first experimental model of FSGS in mice. The activities of antioxidant enzymes including catalase, GPX and Mn-SOD and the glutathione concentration in renal cortex were decreased by ADR nephropathy in BALB/c mice . The level of nitric oxide in kidney homogenates , and the urinary levels of nitrite/nitrate  were also increased in the ADR nephropathy model. The administration of the soluble receptor for advanced glycation endproducts (AGEs) suppressed AGE generation and reactive oxygen species in the ADR nephropathy mice .
In the present study, we hypothesized that a defect in the antioxidant system in the form of catalase deficiency would enhance proteinuria, glomerular sclerosis, and eventually lead to the loss of renal function. This hypothesis was tested using the ADR nephropathy model, which is a well-established model of progressive FSGS, in acatalasemic mice.
Experimental animal protocol
Male wild-type mice (C3H/AnLCsaCsa) and male homozygous acatalasemic mutant mice (C3H/AnLCsbCsb) were used at the age of 8 - 10 weeks. Animals were housed in cages and fed standard chow and water ad libitum. ADR (10, 15 and 20 mg/kg BW) dissolved in saline was intravenously administered to both acatalasemic mutant mice and control wild-type mice . In the C3H/AnL strain, the dose of 10 mg/kg BW did not induce significant albuminuria or increase mortality (Additional file 1: Figure S1A). The 20 mg/kg BW dose resulted in a rapid increase in mortality in both groups of mice (Additional file 1: Figure S1C). The ADR-induced cardiotoxicity might have led to the high mortality resulting from the higher dose of ADR . A total of 55.3% of the acatalasemic mice and 59.2% of the wild-type mice survived 8 weeks after the injection of 15 mg/kg BW ADR (Additional file 1: Figure S1B) with a substantial amount of albuminuria. Therefore, 15 mg/kg BW ADR was considered to be a suitable concentration to investigate the effects of a functional catalase deficiency in the ADR nephropathy model. In the control mice, the same volume of saline was injected intravenously.
Mice were divided into subgroups (n = 6-15/group). Their body weight was measured at 0, 4 and 8 weeks. The mice were sacrificed at 0, 4 and 8 weeks after ADR administration, then their kidneys and hearts were harvested, washed with saline, blotted dry on gauze, and weighed as described previously [16, 17]. The whole kidney weight and heart weight were expressed as a percentage of the body weight determined at the time the mice were sacrificed. Twenty-four hour urine samples were collected in metabolic cages every 4 weeks. Immediately before death, blood samples were drawn. The serum creatinine, blood urea nitrogen (BUN), and urinary albumin excretion (UAE) levels were measured, and the creatinine clearance (Ccr) was calculated as described previously . The experimental protocol was approved by the Ethics Review Committees for Animal Experimentation of Okayama University Graduate School (OKU-2009226).
Reagents and antibodies
Chemicals and reagents of analytical grade were purchased from Sigma Co. Ltd. (St. Louis, Missouri) or Wako Pure Chemical Ind. (Osaka, Japan) unless stated otherwise. The mouse monoclonal antibody to 4-hydroxy-2-nonenal (4-HNE) was obtained from Nof Life Science (Tokyo, Japan). The N-histofine MOUSESTAIN KIT was obtained from NICHIREI BIOSCIENCES INC. (Tokyo, Japan). The catalase assay kit was obtained from Cayman (Ann Arbor, Michigan).
Light and electron microscopic studies
The kidneys were removed, fixed in 10% buffered formalin, and embedded in paraffin. Paraffin sections (3-μm thick) were stained with periodic acid-Schiff (PAS) and Masson's trichrome stain. Each tissue section was evaluated under an Olympus light microscope (Olympus, Tokyo, Japan) with a high-resolution digital camera system (Penguin 600CL; Pixera Co., Los Gatos, CA). The area of glomeruli was measured using a Microanalyzer software program (version 1.1, Japan Poladigital Co., Tokyo, Japan) . Glomerulosclerosis was quantified using the percentage increase in the relative mesangial matrix area (the PAS-positive area within the glomerulus divided by the glomerular capillary area; high magnification). All mean values were calculated from 10 glomeruli. Electron microscopy was performed for the mouse kidney specimens as described previously [16, 17]. A quantitative analysis was performed to count the number of podocyte foot processes per 10 μm of glomerular basement membrane in each glomerulus by electron microscopy. The mean number of podocyte foot processes was defined as the effacement score. The area of interstitial fibrosis in the cortex was evaluated with Masson's trichrome as described previously , with some modifications. Under low magnification, the number of casts in five randomly selected non-overlapping fields from the cortical region was counted and averaged as the cast score.
To detect lipid oxidation products, paraffin sections (3-μm thick) were stained using an N-histofine MOUSESTAIN KIT as described previously . A mouse monoclonal antibody to 4-HNE was used as the primary antibody (1:100 dilution). Under low magnification, five randomly selected non-overlapping fields from the cortical region were analyzed. The 4-HNE positive areas that were stained in brown were picked up on digital images, and the percentage of the 4-HNE positive area relative to the whole area of the field was calculated (% area).
Renal catalase activity
Kidney samples were stored in a -80°C freezer until being assayed. The catalase activity in each kidney was determined by an ELISA using a catalase assay kit . All procedures were performed according to the manufacturer's instructions.
Toll-like receptor-4 gene (Tlr4) mutation analysis in exon 3 in wild-type (C3H/AnLCsaCsa) and acatalasemic mice (C3H/AnLCsbCsb)
The detection of the Tlr4 mutation was performed using nested-PCR as described previously . The nested PCR for detection of the missense mutation, a C to A transversion (Pro712His), which was reported in the C3H/HeJ mouse strain , was performed using the primers shown in Additional file 2: Table S1. The primers TLR4-ex3-F and TLR4-ex3-R were used for direct sequencing of DNA extracted from the mouse kidneys.
The data were shown as the means ± SE. The normal distribution and homogeneity of variance were checked, and logarithmic transformations were made for the variables if needed. Multiple comparisons between groups were made by Scheffe's test or the Steel-Dwass test. A Kaplan-Meier analysis and the Log-Rank statistic were used to explore the effects of ADR in both groups of mice. The statistical analysis was performed using the Excel add-in software Statcel 2 program (OMS, Tokyo, Japan) or the JMP 9 software program (SAS Institute Inc., Cary, North Carolina). P < 0.05 denoted the presence of a statistically significant difference.
Changes in body weight, kidney weight, and heart weight in the mouse ADR nephropathy model
The metabolic and laboratory data of the mice
Body weight (g)
29.1 ± 0.50
29.6 ± 0.41
24.8 ± 0.97a, c
28.0 ± 0.40
28.2 ± 0.31
24.1 ± 0.84b, d
Relative kidney weight (% of body wt)
1.68 ± 0.05
1.67 ± 0.04
1.70 ± 0.13
1.94 ± 0.04
1.66 ± 0.04
1.30 ± 0.08b, c, e
Relative heart weight (% of body wt)
0.38 ± 0.02
0.48 ± 0.02
0.48 ± 0.05
0.43 ± 0.03
0.52 ± 0.01
0.40 ± 0.03
Blood urea nitrogen (mg/dl)
23.8 ± 1.29
26.4 ± 0.77
25.6 ± 4.31
26.0 ± 1.02
26.7 ± 2.56
32.6 ± 4.16
Creatinine clearance (μl/min/g BW)
2.68 ± 0.81
3.80 ± 0.99
2.10 ± 0.77
3.53 ± 1.27
3.21 ± 1.13
1.61 ± 0.61
The increase in albuminuria is significantly accelerated in acatalasemic mice after ADR administration
Acatalasemia accelerates glomerulosclerosis and tubulointerstitial fibrosis
Acatalasemia enhances the accumulation of lipid peroxides in the kidneys of the ADR nephropathy model mice
The catalase activity in acatalasemic ADR nephropathy kidneys did not significantly change
Toll-like receptor-4 mutation analysis
To examine the background of the mouse strains, we performed a mutation analysis of Tlr4 exon 3. Tlr4 did not show a C to A transversion due to a missense mutation in the C3H/AnL mouse strain, which was reported to be present in the C3H/HeJ strain (Additional file 4: Figure S3) .
In the present study, acatalasemic mouse strains deficient in catalase activity were used as an animal model. These mice were found to be more susceptible to functional and morphological alterations in the kidneys induced by adriamycin than wild-type mice. The level of albuminuria and glomerulosclerosis in the acatalasemic mice after adriamycin injection was significantly higher than that in the wild-type mice. The renal catalase activity in these mice remained low, without compensatory upregulation of GPX or SOD. Collectively, these data suggest that the increased ROS, particularly the hydroxyl radical, resulting from the reduction of catalase activity, may be involved in the acceleration of glomerulosclerosis found under acatalasemic disease conditions.
Although some rat strains show complete susceptibility to ADR, most mouse strains do not. Zheng et al. showed that AKR/J, C3H/HeJ, CBA/J, C57BL/10J, LP/J, SWR/J, SJL/J, and 129S6/SvEvTac mice were resistant to ADR nephropathy, whereas 129S1/SvImJ and BALB/cByJ mice were susceptible [26, 27]. They also showed that the susceptible allele for the adriamycin was present in the DOXNPH locus . We did not confirm whether this allele is present in the C3H/AnL mouse strain. Instead, we performed a mutation analysis of the TLR4 gene, because it has been thought that TLR4 is involved in progressive renal fibrosis . TLR4 is considered to be the critical component of the LPS receptor complex. In 1998, a point mutation in the TLR4 gene was found to be the molecular basis of the LPS hyporesponsiveness in C3H/HeJ mice . The C3H/AnL mice used in the present study did not have this mutation. Therefore, ADR induced mild renal fibrosis in both groups, although the degree of interstitial fibrosis was only significant in the acatalasemic mice.
ADR induced severe albuminuria, thus leading to values ranging from 23 to 226 mg/mgCr in BALB/cj mice and a value of 0.04 mg/gCr in B6/D2 mice . In our study, ADR induced relatively mild albuminuria, with 0.6 mg/mgCr in wild-type and 1.5 mg/mgCr in acatalasemic mice. The C3H/AnL mouse strain is considered to have mild sensitivity to ADR. A single dose of ADR (9.5 mg/kg BW) brought about 40% segmental glomerulosclerosis in the BALB/c mouse strain in a previous study . The wild-type mice which we used in this study had only 15% segmental glomerulosclerosis at week 8 after administration, while the acatalasemic mice had 20% glomerulosclerosis at week 8. This indicates that when the catalase activity is decreased, the resistance to ADR is diminished, and segmental glomerulosclerosis is induced. The number of foot processes of the podocytes did not differ between the mouse groups, indicating that the foot process effacement of the podocytes was affected to a similar degree in both mouse groups. The discrepancy between the level of albuminuria and the degree of foot process effacement may be due to the fact that this evaluation procedure compares only the surviving podocytes in the unsclerosed glomerulus.
Noiri et al. previously investigated the percentage of cortical interstitial volume in the ADR model , and Turnberg et al. evaluated tubulointerstitial injury, including cast formation . We evaluated the presence of tubulointerstitial injury in similar analyses, and found significant tubulointerstitial injury only in the acatalasemic mice. The fact that acatalasemia exacerbates pulmonary fibrosis in bleomycin-induced lung injury  and chlorhexidine gluconate-induced peritoneal fibrosis  was already demonstrated. In this study, we showed that acatalasemia exacerbates renal fibrosis in a murine FSGS model.
The overexpression of catalase prevented albuminuria and interstitial fibrosis in the angiotensinogen transgenic mice . In our study, the deficiency of catalase accelerated the albuminuria and glomerular sclerosis in the ADR nephropathy model. These data suggest that reactive oxygen species may contribute to progressive renal injury. Injac et al. reported that the activity of catalase, which detoxifies hydrogen peroxide to H2O, was increased after ADR administration in rats . We measured the catalase activity in the whole kidneys of wild-type mice, and found that its level increased after ADR administration. Therefore, the differences in the albuminuria and the degree of glomerulosclerosis between wild-type and acatalasemic mice may be due to the significant difference of catalase activity in kidneys in these mice and the inability of the acatalasemic mice to increase catalase activity under oxidative stress.
Sheerin et al. reported that ADR-injected mice that died in the complement protein C3+/+ group at 6 weeks had a high serum urea level prior to death . In the current study, all mice survived for at least 4 weeks after the injection of 15 mg/kg BW ADR; however 44.7% of the acatalasemic mice and 40.8% of the wild-type mice died 8 weeks after the administration of ADR. These mortality rates were not significantly different between the two groups (Additional file 1: Figure S1B). Since the incidence of albuminuria was analyzed in all of the mice that had survived at 8 weeks, but histological studies were not performed in more than half of the mice that survived at 8 weeks, bias might have been introduced into the analysis. We did not take blood samples or evaluate the serum urea levels in ADR-treated mice that died just before the end of the 8 weeks in this study. In addition, the administration of ADR can cause cardiotoxicity  and gastrointestinal toxicity in mice , however we could not confirm these toxicities in our experiments.
Acatalasemia is a rare human disease [3, 39]. It is unknown whether albuminuria and glomerulosclerosis are related to low catalase activity in humans, although the total antioxidant capacity is correlated with albuminemia, and inversely correlated with proteinuria and anti-DNA antibodies in subjects with lupus nephritis . In addition, apoptosis, which is thought to be related to oxidative stress, correlated with the immunoserological activities of lupus nephritis  and idiopathic early FSGS . However, the mechanism(s) by which oxidative stress influences human renal disease is largely unknown. Further studies are needed to elucidate whether and how a low catalase activity in humans influences either albuminuria or glomerulosclerosis associated with kidney diseases.
We herein demonstrated that ADR induced more albuminuria and glomerulosclerosis in catalase-deficient mice. Treatment with catalase supplementation may contribute to the suppression of progressive renal injury with proteinuria and glomerulosclerosis.
We thank Ms. T. Hashimoto, Y. Sato and S. Kameshima for their valuable technical assistance and Ms. Ariyoshi for maintaining the acatalasemic mouse strains. We also are grateful to Dr. H. A. Uchida for his excellent advice on the tlr4 mutation analysis. A portion of this study was supported by a Grant-in-Aid for Progressive Renal Diseases Research, Research on Intractable Disease, from the Ministry of Health, Labor and Welfare of Japan.
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