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Adriamycin induces a nephrotic syndrome in rats characterized by severe ultrastructural changes of visceral epithelial cells similar to those observed in puromycin aminonucleoside (PA) nephrosis and in human 'minimal changes' glomerulopathy. Since steroids have been shown to be effective in human 'minimal changes' glomerulopathy and in PA nephrosis, we undertook the present study to assess whether steroids had a therapeutic effect on adriamycin nephrosis. Groups of rats injected with different doses of adriamycin were subsequently treated with prednisolone. No significant differences were observed in proteinuria and in ultrastructural findings between the control and the steroid-injected animals. This study suggests that the mechanism underlying adriamycin-induced nephrotic syndrome might be different from that responsible for PA nephrosis or human 'minimal changes' glomerulopathy.
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... Both of these traits are generally considered to have multifactorial determination, complicating efforts to distinguish contributions of single genes. Anthracycline-induced nephropathy represents an interesting and unusual combination of these phenotypes, revealing a unique vulnerability to anthracycline toxicity in renal podocytes of susceptible rodent strains and some humans (6)(7)(8)(9)(10)(11)(12)(13). Prior data suggest that this trait is likely autonomous to the kidney: podocyte damage and glomerulosclerosis can be prevented by transient clipping of the renal artery during drug injection, suggesting that initial exposure to the anthracycline, rather than its metabolites, causes nephropathy (7,14). ...
The development of kidney disease is influenced by both genetic and environmental factors. Searching for models of glomerulopathy that display strong gene–environment interaction, we examined the determinants of anthracycline-induced nephropathy, a classic, strain-dependent experimental model applied to rodents in the past four decades. We produced three crosses derived from mice with contrasting susceptibility to doxorubicin (DOX) nephropathy and, surprisingly, we found that this widely studied model segregates as a single-gene defect with recessive inheritance. By genome-wide analysis of linkage, we mapped the trait locus to chromosome 16A1-B1 (DOXNPH locus) in all three crosses [peak logarithm of odds (lod) score of 92.7, P = 1 × 10⁻⁶⁵]; this interval represents a susceptibility locus for nephropathy. Gene expression analysis indicated that susceptibility alleles at the DOXNPH locus are associated with blunted expression of protein arginine methyltransferase 7 (Prmt7) on chromosome 8, a protein previously implicated in cellular sensitivity to chemotherapeutic agents (lod = 12.4, P = 0.0001). Therefore, Prmt7 expression serves as a molecular marker for susceptibility to DOX nephropathy. Finally, increased variation in the severity of kidney disease among affected mice motivated a second genome-wide search, identifying a locus on chromosome 9 that influences the severity and progression of nephropathy (DOXmod, peak lod score 4.3, P = 0.0018). These data provide genetic and molecular characterization of a previously unrecognized Mendelian trait. Elucidation of DOX nephropathy may simultaneously provide insight into the pathogenesis of renal failure and mechanisms of cytotoxicity induced by chemotherapeutic agents.
... For example, a study using a rat PAN injury model of MCD showed a dose-dependent beneficial effect of glucocorticoids that correlated with restoration of key podocyte differentiation markers as well as phosphorylation of the GR 24 . By contrast, glucocorticoids were ineffective in an Adriamycin-induced rat model of nephrotic syndrome reflective of focal segmental glomerulosclerosis (FSGS) 25 . As mice are generally resistant to PAN-induced nephrosis 26 , studying glucocorticoid responsiveness in mouse models is challenging. ...
Nuclear receptors have a broad spectrum of biological functions in normal physiology and in the pathology of various diseases, including glomerular disease. The primary therapies for many glomerular diseases are glucocorticoids, which exert their immunosuppressive and direct podocyte protective effects via the glucocorticoid receptor (GR). As glucocorticoids are associated with important adverse effects and a substantial proportion of patients show resistance to these therapies, the beneficial effects of selective GR modulators are now being explored. Peroxisome proliferator-activated receptor-γ (PPARγ) agonism using thiazolidinediones has potent podocyte cytoprotective and nephroprotective effects. Repurposing of thiazolidinediones or identification of novel PPARγ modulators are potential strategies to treat non-diabetic glomerular disease. Retinoic acid receptor-α is the key mediator of the renal protective effects of retinoic acid, and repair of the endogenous retinoic acid pathway offers another potential therapeutic strategy for glomerular disease. Vitamin D receptor, oestrogen receptor and mineralocorticoid receptor modulators regulate podocyte injury in experimental models. Further studies are needed to better understand the mechanisms of these nuclear receptors, evaluate their synergistic pathways and identify their novel modulators. Here, we focus on the role of nuclear receptors in podocyte biology and non-diabetic glomerular disease.
Contrast-induced nephropathy (CIN) is a major adverse event in patients undergoing coronary angiography. The Mehran risk model is the gold-standard for CIN risk prediction. However, its performance in comparison to more contemporary National Cardiovascular Data Registry-Acute Kidney Injury (NCDR-AKI) risk models remains unknown. We aimed to compare both in this study.
Methods and results
Predictions of Mehran and NCDR-AKI risk models and clinical events of CIN and need for dialysis were assessed in a total of 2067 patients undergoing coronary angiography with or without percutaneous coronary intervention. Risk models were compared regarding discrimination (receiver operating characteristic analysis), net reclassification improvement (NRI) and calibration (graphical and statistical analysis). The NCDR risk model showed superior risk discrimination for predicting CIN (NCDR c-index 0.75, 95% CI 0.72–0.78; vs. Mehran c-index 0.69, 95% CI 0.66–0.72, p < 0.01), and continuous NRI (0.22; 95% CI 0.12–0.32; p < 0.01) compared to the Mehran model. The NCDR risk model tended to underestimate the risk of CIN, while the Mehran model was more evenly calibrated. For the prediction of need for dialysis, NCDR-AKI-D also discriminated risk better (c-index 0.85, 95% CI 0.79–0.91; vs. Mehran c-index 0.75, 95% CI 0.66–0.84; p NCDRvsMehran < 0.01), but continuous NRI showed no benefit and calibration analysis revealed an underestimation of dialysis risk.
In German patients undergoing coronary angiography, the modern NCDR risk model for predicting contrast-induced nephropathy showed superior discrimination compared to the GRACE model while showing less accurate calibration. Results for the outcome ‘need for dialysis’ were equivocal.
The administration of glucocorticoids has been reported to exacerbate proteinuria in a few patients with glomerulonephritis. This effect has not been well recognized, and the pathogenetic mechanism responsible for this phenomenon remains to be clarified. In this study, we observed that a high daily oral dose (0.5 mg/kg body weight) of dexamethasone was capable of inducing overt proteinuria in mice, beginning on day 5 and persisting for a 19-day duration. One fourth of mice also intermittently presented with slight hematuria beginning on day 12. Renal lesions in the dexamethasone-treated mice, which were killed on day 23, were characterized by mild mesangial expansion, segmental or global hyalinosis/sclerosis in deep cortical glomeruli, and focal tubular changes. No glomerular inflammatory cell infiltration or proliferative lesion was noted in any of the mice. Ultrastructural features of glomeruli included mesangial widening characterized by either an increase of mesangial matrix, dilated mesangial channels filled with slightly electron-dense material or mesangial lysis-like appearance showing intracytoplasmic microcysts filled with electron-lucent material, and evidence to support injury of endothelial cells, erythrocytes, and podocytes. An immunofluorescence study revealed enhanced glomerular deposition of IgG, IgA, IgM, and fibrinogen (P < 0.001, compared with normal control mice), but no glomerular C3 deposition was identified in any of the dexamethasone-treated mice. Charge analysis showed no impairment in anionic property of glomerular tufts in the dexamethasone-treated mice. In addition, the dexamethasone-induced proteinuria was greatly attenuated by treatment with a low molecular weight heparin, although it was not reduced by an angiotensin-converting enzyme inhibitor. Data from these experiments suggest that a large dose of glucocorticoids is potentially nephrotoxic. Alteration of a size-dependent permeability may predominantly contribute to the dexamethasone-induced proteinuria. However, the effect of glomerular hyperfiltration may be only partially involved in the pathogenesis of this dexamethasone-induced glomerulopathy in mice.
The present paper presents a morphometric study of the evolution of the glomerulus in Adriamycin-induced focal and segmental glomerulosclerosis in the rat over 32 weeks. The morphometric parameters studied generally varied significantly when the groups treated with Adriamycin were compared with controls. Glomerular area and perimeter showed an irregular pattern and finally ended up with values similar to those of the control group. Glomerular capillary tuft area and perimeter were always significantly greater in Adriamycin-treated groups than in controls. The mesangial area of treated animals increased over the study period in comparison with that of controls. While the total number of cells in the glomerular capillary tuft had an irregular pattern, the proportion of cells in relation to glomerular capillary tuft area was significantly lower in treated animals than in controls.
The hydroxyl radical scavengers dimethylthiourea (DMTU), sodium benzoate, and dimethylsulfoxide (DMSO) were administered to rats before doxorubicin hydrochloride (ADR) (5 mg/kg, IV) to probe the role of free radicals in mediating proteinuria in doxorubicin hydrochloride nephrosis (AN). Because ADR stimulates free radical production, the role of renal glutathione was also evaluated; glutathione metabolism is involved in tissue detoxification processes. DMTU administration to rats with AN caused a significant (p less than 0.01) reduction in their proteinuria after 7 days (52.84 +/- 13.21 mg/24 hours) when they were compared with ADR controls (155.81 +/- 20.16 mg/24 hours). In similar fashion, their urine albumin excretion was also significantly reduced when compared with that of ADR controls (11.13 +/- 2.75 mg/24 hours vs 32.08 +/- 4.14 mg/24 hours; p less than 0.01). DMTU-treated rats also had significantly (p less than 0.001) reduced urinary protein and albumin excretion at 14 days when compared with rats that received ADR alone. The urinary excretion of lysozyme and N-acetyl-glucosaminidase, markers of renal tubular injury, were significantly increased after 7 or 14 days in rats with AN, despite DMTU treatment. Creatinine clearance was significantly reduced (p less than 0.05) in rats receiving ADR alone (0.223 +/- 0.011 ml/min/100 gm) when compared with that in normal controls (0.331 +/- 0.027 ml/min/100 gm) or DMTU-treated rats (0.289 +/- 0.035 ml/min/100 gm). Unlike DMTU, neither sodium benzoate nor DMSO reduced proteinuria in rats with AN.(ABSTRACT TRUNCATED AT 250 WORDS)
Tissue and plasma levels of thiobarbituric acid reactive substances (TBARS) were measured in rats treated chronically with doxorubicin. In addition, heart creatine phosphokinase and antioxidant defenses were examined. Male rats received doxorubicin (DXR) 2 mg/kg or vehicle weekly subcutaneously for 13 weeks and were sacrificed at 14 and 19 weeks, 1 and 6 weeks after the last dose, respectively. Histological evaluation in DXR-treated rats at 14 and 19 weeks found significant and progressive cardiac and renal lesions as compared to controls. Heart TBARS were unchanged from controls. Plasma and kidney levels of TBARS were elevated above controls at both 14 and 19 weeks. Lung levels of TBARS were significantly elevated above controls at 14 weeks. Liver levels of TBARS were elevated at 19 weeks. Heart creatine phosphokinase activity was significantly depressed from controls at both 14 and 19 weeks. Heart glutathione peroxidase and superoxide dismutase activities were unchanged from controls. Heart glutathione, glutathione reductase, glucose-6-phosphate dehydrogenase, and catalase were elevated above controls at both 14 and 19 weeks. The lack of change in heart TBARS suggests that changes in TBARS in other organs may be secondary processes. The depression of creatine phosphokinase suggests that levels of adenosine triphosphate may be insufficient to sustain the myocardial function and this may partly be responsible for DXR-induced cardiac myopathy.
The effects of multiple doses of doxorubicin (DXR) on hematocrit and plasma levels of prostaglandins (PG), thromboxane B2 (TxB2), total lipid, esterified and free fatty acids, and proteins were investigated in male rats. The rats received DXR (2 mg/kg) or vehicle weekly by the subcutaneous route for 2, 4, 8, and 13 weeks and were killed 1 week after their last dose. Another group of rats treated for 13 weeks was sacrificed at 19 weeks, 6 weeks after the last dose. No changes in hematocrit or plasma PG, TxB2, or total levels of fatty acids were noted between control and DXR-treated rats at either 3, 5, or 9 weeks. The hematocrit was slightly depressed from control levels at 14 and 19 weeks. Plasma PGE, PGF2 alpha, and TxB2 were elevated over control levels at 14 and 19 weeks. Plasma 6-keto-PGF1 alpha was increased over the control level only at 19 weeks. Total plasma lipid and esterified fatty acids were highly elevated over control levels at 14 and 19 weeks. Plasma free arachidonic acid was elevated over control levels at 14 and 19 weeks, while levels of other free fatty acids were unchanged. Plasma protein levels were slightly depressed from control levels at 3, 9, and 14 weeks. Elevations of plasma free arachidonic acid, PG, TxB2, esterified fatty acids, and total lipid might be involved in cardiotoxicity and nephrotoxicity found with chronic administration of DXR.
This review attempts an analysis of the major components which make it extremely difficult to extrapolate toxicological data obtained with chemicals from animals to man. A first problem concerns the use of doses to express the unit of comparison across animal species; the dose is a parameter exogenous to the body and when a chemical enters the body concentrations should be utilized. There is in fact evidence that for several chemicals equal doses in different animal species do not mean equal concentrations in blood or tissues. Concentrations of chemicals should be measured for extrapolation purposes as close as possible to the site of the toxic effect. A second problem regards the fact that several chemical are transformed in the body into other chemical species--sometimes few and sometimes many--and some of these species (active metabolites) display biological activity in some cases higher than different from or antagonistic to those of the parent compounds. Some of these metabolites are highly reactive and therefore bind to body components, particularly macromolecules such as proteins and nucleic acids. There is evidence that metabolism is quantitatively and/or qualitatively different in various animal species. A third problem concerns the difference in various animal species in the biological substrates on which chemicals exert their toxic effects. Equal concentrations of chemicals and their metabolites do not mean equal toxic effects across animal species because endogenous metabolic processes, cell permeability, enzymes, and receptors are not necessarily the same in animals and man. To overcome these difficulties there is a need for closer integration of different disciplines in the toxicological evaluation of chemicals. A scientific rather than a routine approach in toxicology is emphasized.
The synergistic effects of combining fish oil (FO) diet, which reduces thromboxane A production, with the free radical scavenger, dimethylthiourea (DMTU), were evaluated in acute adriamycin nephrosis, because proteinuria in adriamycin nephrosis is mediated by increased renal thromboxane A and free radical production. The effects of combined evening primrose oil (EPO) and DMTU were compared with the DMTU + FO combination because EPO increases prostaglandin E but not thromboxane A. After 7, 14, and 21 days, proteinuria was significantly (p < 0.05) reduced in rats receiving either DMTU + corn oil (CO) or DMTU + FO compared with untreated control rats. However, after 21 days, rats receiving DMTU + FO had significantly reduced urine protein excretion compared with those receiving DMTU + CO (103.9 +/- 20 mg daily vs 351.8 +/- 29.8 mg daily; P < 0.05). In contrast to FO, rats receiving EPO + DMTU had similar urine protein excretion to rats receiving DMTU + CO after 21 days (170.2 +/- 20.34 mg daily vs 179.45 +/- 26.38 mg daily). The mean serum cholesterol concentration was significantly (P < 0.01) reduced in rats receiving DMTU + FO (195.2 +/- 23.8 mg/dL) compared with DMTU + CO (377.9 +/- 28.5 mg/dL). Serum triglyceride levels also were significantly (P < 0.01) reduced in rats receiving DMTU + FO (52.5 +/- 26.4 mg/dL) compared with DMTU + CO (100.5 +/- 36.9 mg/dL). No significant differences in serum cholesterol concentrations or triglycerides occurred between rats receiving DMTU + CO and DMTU + EPO. Renal glutathione content was significantly (P < 0.05) increased by 23% in normal rats receiving FO diet and by 34% in rats receiving combined DMTU + FO compared with CO alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Although a lot of animal models of proteinuria have been established, proposals for the mechanisms of proteinuria are still controversial. In this work, during an 18-day trial, mice injected with a single dose of adriamycin (AD) rapidly showed combined glomerular albuminuria and immunoglobulinuria, progressively elevated levels of nitrite/nitrate in urine, hypercholesterolemia, abnormal renal function, segmentally or globally glomerular hyalinosis/sclerosis associated with tubular atrophy, enhanced glomerular deposition of immunoglobulins and fibrinogen, augmented expression of matrix components in the whole glomerular tuft, and loss of glomerular negative charge property. These laboratory and pathological features are comparatively similar to those of human focal segmental glomerulosclerosis in the advanced state. Juxtamedullary glomeruli appear to be more susceptible to the AD-related nephrotoxicity than those in the superficial renal cortex. A change in size-dependent glomerular permselectivity may precede a charge-dependent defect in glomeruli in this mouse model of proteinuria. Data in this study confirm the hypothesis of glomerular hyperfiltration involved in the pathogenesis of this chronic glomerulopathy associated with proteinuria in mice. In addition, nitric oxide may play a crucial role in the progression of the chronic glomerulopathy model.
Doxorubicin (DXR) is an anthracycline glycoside with a broad spectrum of therapeutic activity against various tumors. However, the clinical use of DXR has been limited by its undesirable systemic toxicity, especially in the heart and kidney. This study was designed to test the effectiveness of dietary intake of pirfenidone (PD) against DXR-induced cardiac and renal toxicity.
Male Sprague Dawley rats were placed into four treatment groups: saline injected intraperitoneally (i.p.) plus regular diet (SA+RD); DXR i.p. plus regular diet (DXR+RD); saline i.p. plus the same diet mixed with 0.6% PD (SA+PD); and DXR i.p. plus the same diet mixed with 0.6% PD (DXR+PD). The animals were fed regular or regular plus PD diets 3 days prior to i.p. injections of either saline or DXR and continuing throughout the study. A total dose of DXR (16.25 mg/kg) or an equivalent volume of saline was administered in seven injections (2.32 mg/kg per injection) three times per week with an additional dose on the 12th day. At 25 days following the last DXR or saline injection, some animals were anesthetized for the measurement of cardiac and pulmonary function, and others were killed by an overdose of pentobarbital. At the time the animals were killed, abdominal fluid was collected. Kidney and heart were removed, weighed, fixed with 10% formalin or frozen in liquid nitrogen. The fixed tissues were used for histological examination and the frozen tissues were used for biochemical studies.
The average volumes of abdominal fluid in the DXR+RD and DXR+PD groups were 9.42 ml and 3.42 ml and the protein contents of abdominal fluid in the DXR+RD and DXR+PD groups were 218 mg and 70 mg, respectively. A 12.5% mortality occurred in the DXR+RD group as compared to 0% in DXR+PD group. There were no changes in any of the cardiac or pulmonary physiological parameters in any of the four groups. The changes in the heart and kidney of the DXR+RD group included reduction in organ weight, increase in hydroxyproline content of heart, increase in hydroxyproline, and lipid peroxidation in the kidney and plasma, and increase in protein concentration in urine as compared to rats in the control, SA+RD and SA+PD groups. Treatment with PD abrogated the DXR-induced increases in hydroxyproline content in the heart and kidney, lipid peroxidation of the kidney and plasma, and protein content of the urine in the DXR+PD group. DXR treatment alone caused disorganization of cardiac myofibrils, vacuolization of the myofibers, and renal tubular dilation with protein casts in both the cortical and medullary regions. Treatment with PD minimized the DXR-induced histopathological changes of heart and kidney in the DXR+PD group.
Treatment with PD reduced the severity of DXR-induced toxicity as assessed by reduced mortality, diminished volume of recovered fluid in the abdominal cavity, and severity of cardiac and renal lesions at both the biochemical and morphological levels. These results indicate that PD has the potential to prevent DXR-induced cardiac and renal damage in humans on DXR therapy.
In human focal segmental glomerulosclerosis (FSGS), the tubulointerstitial deposition of the complement (C5b-9) membrane attack complex is correlated with interstitial myofibroblast accumulation and proteinuria. Here, we hypothesized that C5b-9 formation regulates renal myofibroblast accumulation in Adriamycin nephropathy.
Adriamycin nephropathy was induced in complement C6-sufficient (C6+) and C6-deficient (C6-) piebold viral glaxo (PVG) rats. Groups of animals (N= 7 to 8 each) were examined on days 21 and 42. A group of C6+ animals, injected with vehicle, served as the control group.
C6+ and C6- rats with Adriamycin nephropathy had equivalent proteinuria. C5b-9 deposition was increased and present on the apical surface of proximal tubular epithelial cells (day 21 and 42) and peritubular region (day 42 only) in C6+ rats with Adriamycin nephropathy, and absent in C6- rats. Peritubular myofibroblast accumulation increased in a time-dependent manner in C6+ proteinuric rats (control 1.2 +/- 0.4; Adriamycin nephropathy day 21 11.0 +/- 0.7; Adriamycin nephropathy day 42 19.8 +/- 1.7 cells per high power field). In C6- rats this increase was blunted by 87% and 56% on days 21 and 42, respectively (P < 0.01), and was associated with reduced interstitial extracellular matrix (ECM) deposition. Tubulointerstitial injury, tubular vimentin and interstitial monocyte accumulation were also reduced in C6- rats with Adriamycin nephropathy on day 21, but not at day 42. In contrast, the increase in periglomerular myofibroblast accumulation and glomerulosclerosis in Adriamycin nephropathy were not altered by C6 deficiency.
These data suggest that glomerular ultrafiltration of complement components and the intratubular formation of C5b-9 is a specific promotor of peritubular myofibroblast accumulation in FSGS.
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