Adriamycin-induced Nephropathy Research Articles

Therapeutic Effect of Artemether in an Experimental Model of Nephrosis

This study was carried out to elucidate the therapeutic efficacy of a new antimalarial drug, artemether, in adriamycin-induced nephropathy. To induce experimental nephrosis, adriamycin was given once by a single intravenous injection through the tail vein. Six days after adriamycin injection, therapeutic protocol was developed by intramuscular (i.m.) administration of 5 mg/kg artemether (ART). The total of i.m. injections were 14, in which five injections were made every day and nine injections were carried out at regular 48-h intervals. The therapeutic protocol was terminated on day 28, and animals were sacrificed on day 49. Our results showed that treatment with ART caused a significant reduction in the level of proteinuria (118 ± 15 vs. 48 ± 21 mg/24 h), urine urea (723 ± 226 vs. 414 ± 185 mg/dL), and urine sodium (38 ± 8 vs. 28 ± 6 mEq/L) compared with nontreated controls. In addition, a decrease in serum cholesterol (250 ± 58 vs. 163 ± 58 mg/dL) and creatinine (1.4 ± 0.2 vs. 0.9 ± 0.2 mg/dL) and an increase in the level of serum albumin (3.3 ± 0.5 vs. 5.6 ± 0.5 g/dL) were significant in the group treated with ART compared with the patient group. Moreover, treatment with ART significantly reduced glomerular PMN and mononuclear cells infiltration, hypercellularity, karyorrhexis, wire loops and hydropic change in the capillary network within the renal cortex, as well as decreased hyalin casts. On the other hand, healthy controls receiving ART showed a significant decrease in amounts of serum triglyceride (174 ± 55 vs. 88 ± 27mg/dL), urine urea (720 ± 113 vs. 511 ± 211 mg/dL), urine sodium (45 ± 5 vs. 26 ± 6 mEq/L), and potassium (71 ± 14 vs. 53 ± 6 mEq/L) compared with the normal group, where significant reduction of urinary excretion of sodium and urea must be considered as a side effect of ART therapy. These data suggest that artemether therapy can ameliorate proteinuria and suppress the progression of glomerular lesions in an experimental model of nephrosis, and that it may be recommended as a lipid-lowering drug.

Effect of compound Biejia Ruangan tablet on expressions of connective tissue growth factor mRNA and protein in kidney tissue of rats with adriamycin-induced nephropathy

To investigate the changes of connective tissue growth factor (CTGF) protein and CTGF mRNA in kidney tissue of rats with adriamycin (ADR)-induced nephropathy and to study the effects of compound Biejia Ruangan tablet (CBJRGT), a traditional Chinese herbal medicine for treatment of liver fibrosis. A rat model of ADR-induced nephropathy after one-sided nephrectomy was established. Forty-five Wistar rats were randomly divided into 5 groups: normal control group, sham-operated group, untreated group, lotensin-treated group and CBJRGT-treated group. Pathological changes of the kidney tissue were observed by microscopy after 10-week drug administration. The expressions of CTGF protein and CTGF mRNA in the kidney tissue were measured by the methods of immunohistochemistry and in situ hybridization. The expressions of CTGF protein and CTGF mRNA in the normal and sham-operated groups were decreased in the intracytoplasm of glomerular mesangial cells, renal tubular epithelial cells and interstitial cells. Compared with the sham-operated group, the expressions of CTGF protein and CTGF mRNA in the untreated group were markedly increased and the development of renal fibrosis in the untreated group could be observed. CBJRGT could significantly decrease the expressions of CTGF protein and CTGF mRNA, and there was no significant difference between CBJRGT-treated group and lotensin-treated group. CBJRGT may suppress the development of fibrosis through down-regulating the expressions of CTGF protein and CTGF mRNA.

Inhibition of p38 Mitogen-Activated Protein Kinase and Transforming Growth Factor-β1/Smad Signaling Pathways Modulates the Development of Fibrosis in Adriamycin-Induced Nephropathy

Inflammation and fibrogenesis are the two determinants of the progression of renal fibrosis, the common pathway leading to end-stage renal disease. The p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-beta1/Smad signaling pathways play critical roles in inflammation and fibrogenesis, respectively. The present study examined the beneficial renoprotective effect of combination therapy using the p38 MAPK pathway inhibitor (SB203580) and a TGF-beta receptor I (ALK5) inhibitor (ALK5I) in a mouse model of adriamycin (ADR) nephrosis. The p38 MAPK and TGF-beta1/Smad2 signaling pathways were activated in ADR-induced nephropathy in a sequential time course manner. Two weeks after ADR injection, the combined administration of SB203580 (1 mg/kg/24 hours) and ALK5I (1 mg/kg/24 hours) markedly reduced p38 MAPK and Smad2 activities. Moreover, the co-administration of SB203580 and ALK5I to ADR-injected mice resulted in a down-regulation of total and active TGF-beta1 production, reduced myofibroblast accumulation, and decreased expression of collagen type IV and fibronectin. In these mice, retardation in the development of glomerulosclerosis and interstitial fibrosis was observed. In conclusion, although p38 MAPK and TGF-beta1/Smad signaling pathways are distinct they coordinate the progression of renal fibrosis in ADR nephrosis. The co-administration of a p38 MAPK inhibitor and an ALK5 inhibitor may have potential applications in the treatment of renal fibrosis.

Adriamycin nephropathy in severe combined immunodeficient (SCID) mice

Experimental focal glomerulosclerosis is a model of chronic proteinuric renal disease that has been induced in both rats and mice. In mice, the adriamycin (ADR)induced nephropathy model is a robust experimental analogue of human focal glomerulosclerosis [1]. Renal injury in the ADR-induced nephropathy model is characterized by changes in both the tubulointerstitial and glomerular compartments. Within the interstitium, there is an increase in interstitial volume, tubular atrophy, collagen deposition and increased numbers of CD4þ T cells, CD8þ T cells and macrophages [1]. In mice with established adriamycin nephropathy, depletion of CD4þ T lymphocytes worsens glomerular and interstitial injury [2] whilst depletion of CD8þ T lymphocytes ameliorates disease [3]. Therefore, lymphocytes play a pivotal role in renal injury in adriamycin nephropathy (AN). The tubulointerstitium also contains other inflammatory cells such as macrophages, dendritic cells and NK cells. Using lymphocyte-deplete animals enables study of the individual contribution of these cell populations to renal injury. SCID (severe combined immunodeficient) mice are homozygous for an autosomal recessive mutation that leads to the absence of lymphocytes and hypogammaglobulinaemia [4], and are found in BALB/c mice. Adriamycin nephropathy can be induced in immunocompetent BALB/c mice [1]. Previous studies in our laboratory have shown that NK cells do not play a significant role in this model [5]. The aim of the present study was to determine if the model of AN could be established in SCID mice. We found that tail-vein injection of adriamycin induces a stable and reproducible model of proteinuric renal disease in lymphocyte-deplete BALB/c mice at half the dose required for immunocompetent BALB/c mice.

Sequential Extracellular Matrix-focused and Baited-global Cluster Analysis of Serial Transcriptomic Profiles Identifies Candidate Modulators of Renal Tubulointerstitial Fibrosis in Murine Adriamycin-induced Nephropathy

Transcriptome analysis using microarray technology represents a powerful unbiased approach for delineating pathogenic mechanisms in disease. Here molecular mechanisms of renal tubulointerstitial fibrosis (TIF) were probed by monitoring changes in the renal transcriptome in a glomerular disease-dependent model of TIF (adriamycin nephropathy) using Affymetrix (mu74av2) microarray coupled with sequential primary biological function-focused and secondary "baited"-global cluster analysis of gene expression profiles. Primary cluster analysis focused on mRNAs encoding matrix proteins and modulators of matrix turnover as classified by Onto-Compare and Gene Ontology and identified both molecules and pathways already implicated in the pathogenesis of TIF (e.g. transforming growth factor beta1-CTGF-fibronectin-1 pathway) and novel TIF-associated genes (e.g. SPARC and Matrilin-2). Specific gene expression patterns identified by primary extracellular matrix-focused cluster analysis were then used as bioinformatic bait in secondary global clustering, with which to search the renal transcriptome for novel modulators of TIF. Among the genes clustering with ECM proteins in the latter analysis were endoglin, clusterin, and gelsolin. In several notable cases (e.g. claudin-1 and meprin-1beta) the pattern of gene expression identified in adriamycin nephropathy in vivo was replicated during transdifferentiation of renal tubule epithelial cells to a fibroblast-like phenotype in vitro on exposure to transforming growth factor-beta and epidermal growth factor suggesting a role in fibrogenesis. The further exploration of these complex gene networks should shed light on the core molecular pathways that underpin TIF in renal disease.

Effects of pentoxifylline in Adriamycin-induced renal disease in rats

Tumor necrosis factor-alpha (TNF-alpha) is a mediator of inflammation in human and animal renal disease. Pentoxiphylline (PTX) is an inhibitor of TNF-alpha. In this study we examined the effects of PTX on TNF-alpha, proteinuria, nitrite production, and apoptosis in an experimental model of Adriamycin (ADR) nephropathy in rats. Rats were divided into four groups: untreated Wistar rats (controls), PTX treatment alone, ADR treatment alone to induce nephropathy, and ADR treatment followed by PTX. ADR treatment followed by PTX treatment prevented the increase in serum TNF-alpha levels and proteinuria in rats with ADR-nephropathy ( P<0.05). Urine nitrite levels were significantly increased in the ADR-induced nephropathy group and the increase was prevented in the ADR-induced nephropathy group when they also received PTX. The urine nitrite levels were not different between the PTX-treated group and the untreated control rats. PTX prevented the rise of serum TNF-alpha in ADR nephropathy rats and a decrease in proteinuria, urine nitrite, and apoptosis in the renal tissue. These findings suggest a beneficial anti-inflammatory effect of PTX.

Lipocalin-Type Prostaglandin D Synthase in Urine in Adriamycin-Induced Nephropathy of Mice

Background/Aims: Lipocalin-type prostaglandin D synthase (L-PGDS), an enzyme converting prostaglandin H₂ to prostaglandin D₂, occurs particularly in the cardiovascular system. Urinary L-PGDS excretion is increased in diabetes prior to overt proteinuria, suggesting that it is a predictor of renal injury. In this study, we tested the hypothesis that L-PGDS excretion reflects renal injury in primary glomerular diseases using Adriamycin-induced nephropathy in mice. Methods: Twenty 6-week-old ICR female mice were intravenously given a dose of 25 mg Adriamycin/kg body weight through the tail vein. 24-hour urine was collected every day, and blood samples were obtained. Results: The mice developed significant albuminuria from day 3 onward (p < 0.05), which was followed by overt proteinuria from day 4 (p < 0.05). Histological examination revealed focal mesangial expansion with partial tubular atrophy. Urinary L-PGDS excretion significantly increased from day 1 onward (p < 0.05), and apparently preceded the increase in urinary albumin excretions. Either serum L-PGDS or creatinine levels were not changed by administration of Adriamycin. However, serum creatinine levels were inversely correlated to urinary L-PGDS excretions (r = –0.88, p < 0.05). Immunohistochemistry showed that L-PGDS occurred in the tubules, but not in the glomeruli in Adriamycin mice and L-PGDS mRNA paralleled urinary L-PGDS excretion. Conclusion: Urinary L-PGDS excretion is increased in Adriamycin-induced nephropathy, and this precedes overt albuminuria.

The Effect of Eriobotrya japonica Seed Extract on Oxidative Stress in Adriamycin-Induced Nephropathy in Rats

Eriobotrya japonica has been used as a medicinal plant for a long time, and its leaves are known to have many physiological actions such as anti-inflammatory, antitussive, and expectoran. In contrast, Eriobotrya japonica seeds are only known to contain amygdalin, and almost no investigations of its pharmacological action have been performed. Moreover, some anticancer agents such as adriamycin cause renal disorders as an adverse effect, and the mechanism of the adverse effect is considered to involve oxidative stress. We have reported that Eriobotrya japonica seed extract has an inhibitory effect on liver disorders. In this study, we prepared a 70% ethanol extract of Eriobotrya japonica seeds and administered the extract to rats with renal disorder induced by a single administration of 7 mg/kg body weight adriamycin, and investigated the usefulness of the extract. Increases in indices of renal function, plasma urea nitrogen, were significantly inhibited in rats treated with the Eriobotrya japonica extract compared to rats treated with tap water. In addition, the renal tissue level of reduced glutathione was significantly high in rats that ingested the extract, while the lipid peroxide levels in plasma and renal tissue were significantly low. However, no effect on renal tissue antioxidative enzymes was observed, suggesting that Eriobotrya japonica seed extract has direct antioxidative action. Based on these findings, Eriobotrya japonica seed extract may be effective in reducing the oxidative stress of adriamycin-induced renal disorder. Therefore, ingestion of Eriobotrya japonica seed extract may contribute to a reduction of the adverse effects of adriamycin.

Lipoic acid as a rescue agent for adriamycin-induced hyperlipidemic nephropathy in rats

Adriamycin [ADR] is a cell independent model of glomerular injury. Hyperlipidemia associated with nephrotic syndrome may play a role in the deterioration of renal function. The study was carried out with adult male albino rats of Wistar strain comprising six rats in each group. Rats were fed with a standard rat pellet diet and were given access to water ad libitum. Group I rats served as controls (0.5 ml/day/rat i.p). Group II rats received ADR (1 mg/kg body weight/day) intravenously through the tail vein. Group III rats were given lipoic acid [LA] (35 mg/kg body weight/day) intraperitoneally. Group IV rats received LA 24 hours prior to the administration of ADR. ADR administered rats showed a significant increase ( p < 0.05) in serum lipids and lipoprotein fractions. However, the kidney of ADR administered rat showed a decline ( p < 0.05) in the content of phospholipids and free fatty acids. Significant ( p < 0.05) alterations were also observed in the activities of lipid metabolizing enzymes Pre-treatment with LA reverted the levels of lipid profiles and serum lipoproteins to near normal. The activities of lipid metabolizing enzymes also showed considerable changes on LA pre-treatment. This study highlights the antilipemic action of LA and its role as a protective agent for hyperlipidemia, associated with ADR induced nephrotic syndrome.

Renal tubular epithelial cell apoptosis is associated with caspase cleavage of the NHE1 Na+/H+ exchanger.

Renal tubular epithelial cell (RTC) apoptosis causes tubular atrophy, a hallmark of renal disease progression. Apoptosis is generally characterized by reduced cell volume and cytosolic pH, but epithelial cells are relatively resistant to shrinkage due to regulatory volume increase, which is mediated by Na(+)/H(+) exchanger (NHE) 1. We investigated whether RTC apoptosis requires caspase cleavage of NHE1. Staurosporine- and hypertonic NaCl-induced RTC apoptosis was associated with cell shrinkage and diminished cytosolic pH, and apoptosis was potentiated by amiloride analogs, suggesting NHE1 activity opposes apoptosis. NHE1-deficient fibroblasts demonstrated increased susceptibility to apoptosis, which was reversed by NHE1 reconstitution. NHE1 expression was markedly decreased in apoptotic RTC due to degradation, and preincubation with peptide caspase antagonists restored NHE1 expression, indicating that NHE1 is degraded by caspases. Recombinant caspase-3 cleaved the in vitro-translated NHE1 cytoplasmic domain into five distinct peptides, identical in molecular weight to NHE1 degradation products derived from staurosporine-stimulated RTC lysates. In vivo, NHE1 loss-of-function C57BL/6.SJL-swe/swe mice with adriamycin-induced nephropathy demonstrated increased RTC apoptosis compared with adriamycin-treated wild-type controls, thereby implicating NHE1 inactivation as a potential mechanism of tubular atrophy. We conclude that NHE1 activity is critical for RTC survival after injury and that caspase cleavage of RTC NHE1 may promote apoptosis and tubular atrophy by preventing compensatory intracellular volume and pH regulation.

Different effects of 22-oxacalcitriol and calcitriol on the course of experimental chronic renal failure

Calcitriol, 1,25(OH)2D3, has been reported to have a beneficial effect on bone histology in patients with predialysis chronic renal failure; however, such treatment involves a risk of hypercalcemia. To investigate the effects of 1,25(OH)2D3 and 22-oxacalcitriol (OCT) on the progression of histologic deterioration, we administered intraperitoneal 1,25(OH)2D3 or OCT, three times a week, to rats with adriamycin-induced progressive renal failure, from the 10th week after the induction of ADR-induced nephropathy. The rats were divided into the following groups: (1) high-dose 1,25(OH)2D3, 0.2 μg/kg (group D3-0.2); (2) low-dose 1,25(OH)2D3, 0.04 μg/kg (group D3-0.04); (3) high-dose OCT, 0.2 μg/kg (group OCT-0.2); (4) low-dose OCT, 0.04 μg/kg (group OCT-0.04); and (5) ADR-induced nephropathy (group ADR). The death rate at week 20 in group D3-0.2 was 50%, significantly higher than the death rates in the other groups, except for group D3-0.04 (P <.05). The serum creatinine and blood urea nitrogen levels were the highest in group D3-0.2, although the difference was not significant. In contrast, in groups OCT-0.2 and OCT-0.04, tubular changes and interstitial volume were smaller than in groups D3-0.2 and D3-0.04 (P <.05). Although calcium deposits increased in group D3-0.2, the difference was not significant. Glomerular expression of transforming growth factor-β1 (TGF-β1) expression was less in groups OCT-0.2 and OCT-0.04 than in groups D3-0.2 and D3-0.04 (P <.05). Glomerular fibronectin expression was less in group OCT-0.2 than in groups D3-0.2 and ADR (P <.05). Tubulointerstitial expression of TGF-β1 was greater in group D3-0.2 than in group ADR and greater in group D3-0.04 than in group OCT-0.04 (P <.05). We conclude that a high dose of 1,25(OH)2D3 accelerated the progressive renal deterioration of ADR-induced nephropathy, and, as a result, OCT was able to attenuate renal histologic lesions. (J Lab Clin Med 2002;140:242-9)

TREATMENT OF EXPERIMENTAL NEPHROSIS BY CULTURE FILTRATE OF CRYPTOCOCCUS NEOFORMANS VAR. GATTII (CneF)

ABSTRACTThe therapeutic effect of the culture filtrate of cryptococcus neoformans var. gattii (CneF) was tested in Adriamycin-induced nephropathy. The CneF was administered at different doses (36, 54 and 90 mg/kg based on carbohydrate concentration), one i.p. injection every 72 hours for a total of 10 injections. The treated patient rats showed a significant reduction in proteinuria, plasma cholesterol concentration, BUN and significant increase in urine creatinine levels. Moreover, treatment with CneF significantly reduced number of glomerular leukocytes and decreased the tubular casts. These data suggest that CneF therapy can ameliorate proteinuria, hypercholesterolemia and suppress the progression of glomerular lesions in experimental model of nephrosis.

EFFECT OF CYCLOSPORINE ON ADRIAMYCIN INDUCED NEPHRITIS

The effects of cyclosporine A (CSA) administration, started as early as renal lesion is induced, on the development of Adriamycin-induced nephropathy were assessed by comparing the time course of this nephropathy in rats receiving CSA with that in non-treated animals (group ADR) over 16 weeks. Throughout the experiment, no significant difference in proteinuria was observed between the groups. At the end of the experiment, there was no significant difference between the groups regarding the frequency of glomerular lesion (Group AADR: Md = 23%, P25 = 15%, P75 = 75%; Group ADR–CSA: Md = 48%, P25 = 11%, P75 = 70%); tubulointerstitial lesion index (Group ADR: Md = 1.5, P25 = 1.0, P75 = 2.5); glomerulosclerosis area (Group ADR = 18.2 ± 4.2%; Group ADR–CSA = 13.2 ± 1.4%); and, interstitial fibrosis area (Group ADR + V: 1.75 ± 0.10%; group ADR–CSA: 1.34 ± 0.09%). In conclusion, CSA, when administered since nephropathy induction does not change the course of the disease.

EFFECT OF MYCOPHENOLATE MOFETIL ON THE PROGRESSION OF ADRIAMYCIN NEPHROPATHY

In order to assess the effects of mycophenolate mofetil (MMF) on the development of adriamycin-induced nephropathy, the development of this nephropathy in rats treated with MMF was compared to that in non-treated animals (group ADR + V) over 28 weeks. At weeks 8, 16 and 20, 24-h proteinuria of the treated group statistically differed from that of the non-treated group. However, no significant difference in proteinuria was observed thereafter between the groups. At the end of the experiment, there was no significant difference between both groups regarding the frequency of glomerular lesion (Group ADR + V: Md = 35%, P25 = 20%, P75 = 68%; Group ADR + MMF: Md = 27%, P25 = 9.5%, P75 = 54%); tubulointerstitial lesion index (Group ADR + V: Md = 7, P25 = 1.5, P75 = 9; Group ADR + MMF: Md = 8, P25 = 2, P75 = 9); glomerulosclerosis area (group ADR + V = 2779 μm2, P25 = 751.8 μm2, P75 = 3115 μm2; Group ADR + MMF = 1147 μm2, P25 = 3969.7 μm2, P75 = 1560 μm2); and, interstitial fibrosis area (Group ADR + V: Md = 218200 μm2, P25 = 78670 μm2, P75 = 282700 μm2 group ADR + MMF: Md = 136000, P25 = 25010, P75 = 255800 μm2). In conclusion, MMF caused a temporary reduction in proteinuria but did not change the severity of the renal lesion observed after 28 weeks.

Association of nitric oxide production and apoptosis in a model of experimental nephropathy.

In recent studies increased amounts of nitric oxide (NO) and apoptosis have been implicated in various pathological conditions in the kidney. We have studied the role of NO and its association with apoptosis in an experimental model of nephrotic syndrome induced by a single injection of adriamycin (ADR). The alteration in the NO pathway was assessed by measuring nitrite levels in serum/urine and by evaluating the changes in vascular reactivity of the isolated perfused rat kidney (IPRK) system. Rats were stratified into control groups and ADR-induced nephropathy groups. These two groups were then divided into: group 1, animals receiving saline; and group 2, animals receiving aminoguanidine (AG) which is a specific inhibitor of inducible-NO synthase. On day 21, rats were sacrificed after obtaining material for biochemical analysis. Histopathological examination of the kidneys of rats treated with ADR revealed focal areas of mesangial proliferation and mild tubulointerstitial inflammation. They also had significantly higher levels of proteinuria compared with control and treatment groups (P < 0.05). Urine nitrite levels were significantly increased in the ADR-nephropathy group (P < 0.05). In the IPRK phenylephrine and acetylcholine related responses were significantly impaired in the ADR-nephropathy group. Apoptosis was not detected in controls. However, in the ADR-nephropathy group, numerous apoptotic cells were identified in the tubulointerstitial areas. Double staining revealed numerous interstitial apoptotic cells to stain for ED1, a marker for monocytes/macrophages. Treatment with AG prevented the impairment of renal vascular bed responses and reduced both urine nitrite levels and apoptosis to control levels. We suggest that interactions between NO and apoptosis are important in the pathogenesis of the ADR-induced nephrosis.

Heparin Treatment Reduces Glomerular Injury in Rats with Adriamycin-Induced Nephropathy but Does Not Modify Tubulointerstitial Damage or the Renal Production of Transforming Growth Factor-Beta

In this study we investigated the effect of heparin on renal injury and renal transforming growth factor-β (TGF-β) production in adriamycin (AD)-injected rats. Thirty-nine female Wistar rats were injected with AD (3.5 mg/kg body weight, i.v.) and 27 with 0.15 M NaCl solution (group C). Fifteen days later we started to inject heparin, 500 U/day, s.c., in 20 of the AD-injected animals (AD-H group). Three months after beginning treatment, urine samples were collected to quantify albumin, creatinine and TGF-β. The rats were killed and the kidneys removed for histological, immunohistochemical, ELISA and RNA studies. All AD-injected animals showed structural renal changes (p < 0.05). However, the glomerular alterations were less intense in rats from group AD-H (p < 0.05). The percentage of glomerulosclerosis was 0.11 ± 0.08 in group C, 14.7 ± 12.8 in group AD (treated only with AD) and 3.42 ± 2.3 in group AD-H. Renal cortex immunostaining for TGF-β and mRNA content of this polypeptide was higher in both groups of animals injected with AD compared to controls (p < 0.05). These animals also presented a higher rate of urinary TGF-β excretion (p < 0.05), which was 202 ± 11 in group C, 1,103 ± 580 in group AD and 1,564 ± 328 pg/mg Ucreat in group AD-H. However, TGF-β activity in the glomerular-conditioned media from the rats of group AD was higher than in the glomerular-conditioned media from the rats of group AD-H. In conclusion, treatment with heparin reduces glomerular damage in rats with AD-induced nephropathy but does not modify tubulointerstitial lesions or the renal production of TGF-β.

Laboratory Study: Effect of Allopurinol in the Course of Adriamycin Induced Nephropathy

The role of superoxide in adriamycin-induced nephropathy (single dose; i.v. 3 mg/kg) has been studied by blocking superoxide synthesis through the administration of allopurinol (500 mg/L in drinking water). In Experiment I (El), allopurinol administration was started 3 days prior to nephropathy induction and continued until day 14. In Experiment II (EII) allopurinol administration was started 2 weeks after nephropathy induction and was maintained until the end of the experiment (26 weeks). Affected glomeruli frequency and tubulointerstitial lesion index (TILI) were determined at Weeks 2 and 4 (El) and Week 26 (EII). In El, the 24 h mean proteinuria in the nephrotic control group (NCG-I) differed from that of the treated nephrotic group (TNG-I) at Week 1 (TNG = 33.3 ± 6.39 mg/24 h; NCG = 59.8 ± 6.3 mg/24 h; p < 0.05) and 2 (NCG-I = 80.0 ± 17.5 mg/24h; TNG-I = 49.1 ± 8.4 mg/24 h; p < 0.05). No glo-merular alterations were observed and TILI medians were not different in both nephrotic groups at week 2 (NCG-I = 1 + TNG = I +) and 4 (NCG = 4+; TNG = 4+). In EII, NCG-JI and TNG-Il presented different 24 h proteinuria values only at Week 6, (136.91 ± 22.23 mg/24 h and 72.66 ± 10.72 mg/24 h, respectively; p < 0.05). Between nephrotic groups, there was no statistical difference in the median of affected glomeruli (CNG-II = 56%; TNG-U = 48%) and TILI (NCG-II = 8+; TNG-II = 9+). Thus, allopurinol was associated with a transient reduction in proteinuria and it did not alter the progression of the nephropathy

Role of Ticlopidine on Adriamycin-Induced Nephropathy

The effect of ticlopidine on rats with adriamycin nephropathy was observed during 26 weeks. In the ticlopidine-treated nephrotic animals (TNG), proteinuria was less than in the untreated nephrotic animals (NG), but this difference was significant only at week 6 (TNG = 47.27 ± 16.52 versus NG = 100.08 ± 13.83 mg/24h, p < 0.01) and week 26 (TNG =157.00 ± 28.73 versus NG = 217.00 ± 21.73 mg/24h, p < 0.01) after ADR injection. NG presented severe tubulointerstitial abnormalities with a tubulointerstitial lesion index of 3+. No diffience in glomerular lesions was observed among the groups (NG median = 6%. TNG median = 4% and TCG median = 2%). The tubulointerstitial lesion index of TNG was less intense (median = 2+) but not different from those of the control groups (CG median = 1+; TCG median = 0+) nor NG (median = 3+). We concluded that the treatment with ticlopidine produced some partially beneficial effects but did not prevent the devdopment of adriamycin-induced nephropathy.

Importance of Early and Continuous Use of Protein Restriction on the Progression of Adriamycin Nephropathy

Three experimental protocols were carried out with the aim of evaluating the role of protein restriction on the progression of the established adriamycin-induced nephropathy, and whether the protective effect of the diet persists after the diet is discontinued. The effect of a low protein diet (LPD) was studied for 6 weeks in protocol 1, 16 weeks in protocol 2 and for 28 weeks in protocol 3. In protocol 3, one group (LL) received LPD and another (NN) was given a normal protein diet (NPD). A third group (LN) received LPD for 16 weeks and then NPD for 12 weeks and a fourth group (NL) was fed NPD for 16 weeks and then LPD for 12 weeks. In protocol 1 the tubulo-interstitial index (TILI) of rots on LPD (Md = 2, P25 = 0.0; P75 = 3.5) after six weeks, was smaller than that of the animals on NPD (Md = 60; P25 = 3.0; P75 = 8.0; p 0.0,5;. In protocol 2, the group taking LPD presented an area of interstitial fihrosis (IF) (Md 0.5%, P25 0.2%; P75 = 1.9%) smaller than that of the NPD group (Md = 6.8%; P25 = 5.2%; P75 = 7.1%; p < 0.05). No significant difference in the area of glomerulosclerosis (GSA) was observed between the animals on LPD (Md = 0.0%; P25 = 0.0%, P75 = 0.0%) and NPD (Md = 0.37%; P25 = 02%, P75 = 1.25%; p > 0.05). In protocol 3, the group LL showed GSA (Md = 1.3%; P25 0.6%, P75 = 2.5%; and IF (Md = 3.6%; P25 = 1.6%; P75 = 5.9%; smaller that those of LN (GSA Md = 10.1%; P25 = 6.6%; P75 = 14.8%; IF:Md = 17.3%; P25 = 14.1%; P75 = 24.5%), NL (GSA:Md = 9.1%; P25 = 5.8%; P75 = 11.7%; IF:Md = 25.0%; P25 = 20.4%; P75 = 50%), and NN (GSA:Md = 6.75%; P25 = 4.9%; P75 = 11.7%; IF:Md = 20.9%; P25 = 16.2%; P75 = 32.4%). In conclusion, in order to be effective, LPD must be introduced early and maintained for a long period of tune.

Podocytes undergo phenotypic changes and express macrophagic-associated markers in idiopathic collapsing glomerulopathy

Podocytes undergo phenotypic changes and express macrophagic-associated markers in idiopathic collapsing glomerulopathy