RESUMO
Mechanical thrombectomy has become the standard treatment for patients with an acute ischemic stroke. In this approach, to remove blood clots, mechanical force is applied using thrombectomy devices, in which the interaction between the clot and the device could significantly affect the clot retrieval performance. It is expected that the finite element method (FEM) could visualize the mechanical interaction by the visualization of the stress transmission from the device to the clot. This research was aimed at verifying the constitutive theory by implementing FEM based on the visco-hyperelastic theory, using a three-dimensional clot model. We used the visco-hyperelastic FEM to reproduce the mechanical behavior of blood clots, as observed in experiments. This study is focused on the mechanical responses of clots under tensile loading and unloading because in mechanical thrombectomy, elongation is assumed to occur locally on the clots during the retrieval process. Several types of cylindrical clots were created by changing the fibrinogen dose. Tensile testing revealed that the stiffness (E0.45-value) of clots with fibrinogen could be more than three times higher than that of clots without fibrinogen. It was also found that the stiffness was not proportional to the fibrinogen dose. By fitting to the theoretical curve, it was revealed that the Mooney-Rivlin model could reproduce the hyperelastic characteristics of clots well. From the stress-relaxation data, the three-chain Maxwell model could accurately fit the experimental viscoelastic data. FEM, taking the theoretical models into account, was then carried out, and the results matched well with the experimental visco-hyperelastic characteristics of clots under tensile load, reproducing the mechanical hysteresis during unloading, the stress dependence on the strain rate, and the time-dependent stress decrease in the stress-relaxation test.
Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Trombose , Elasticidade , Análise de Elementos Finitos , Humanos , Modelos Biológicos , Estresse MecânicoRESUMO
BACKGROUND: Before the androgen target therapy era, flutamide was widely used for castration-resistant prostate cancer in Japan. Enzalutamide is currently the recommended treatment; however, the efficacy and safety of enzalutamide and flutamide after combined androgen blockade therapy with bicalutamide, has not been compared. METHODS: Patients with castration-resistant prostate cancer who received combined androgen blockade therapy with bicalutamide were randomly assigned to receive either enzalutamide or flutamide. The primary endpoint for efficacy was the 3-month prostate-specific antigen response rate. This trial is registered with ClinicalTrials.gov (NCT02346578) and the University hospital Medical Information Network (UMIN000016301). RESULTS: Overall, 103 patients were enrolled. The 3- (80.8% vs. 35.3%; p < 0.001) and 6-month (73.1% vs. 31.4%; p < 0.001) prostate-specific antigen response rates were higher in the enzalutamide than in the flutamide group. The 3-month disease progression rates (radiographic or prostate-specific antigen progression) were 6.4% and 38.8% in the enzalutamide and flutamide groups, respectively [hazard ratio (HR): 0.16; 95% confidence interval (CI): 0.05-0.47; p < 0.001]; the 6-month rates were 11.4% and 51.1%, respectively (HR 0.22; 95% CI 0.09-0.50; p < 0.001). Enzalutamide provided superior prostate-specific antigen progression-free survival compared with flutamide (HR 0.29; 95% CI 0.15-0.54; p < 0.001). Median time to prostate-specific antigen progression-free survival was not reached and was 6.6 months in the enzalutamide and flutamide groups, respectively. CONCLUSIONS: As an alternative anti-androgen therapy in patients with castration-resistant prostate cancer who fail bicalutamide-combined androgen blockade therapy, enzalutamide provides superior clinical outcomes compared with flutamide. Enzalutamide should be preferred over flutamide in these patients.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anilidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Flutamida/administração & dosagem , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Feniltioidantoína/análogos & derivados , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Compostos de Tosil/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: It is recognized that matrix metalloproteinase-3 (MMP-3) is abundantly expressed in active rheumatoid synovium, and that serum level of MMP-3 is a useful marker for diagnosis of rheumatoid arthritis and for evaluation of prognosis in joint destruction. Little is known about serum MMP-3 levels in haemodialysis (HD) patients, and thus, the association between serum MMP-3 and dialysis-related amyloidosis (DRA) has yet to be elucidated. METHODS: Serum levels of MMP-3 were measured by enzyme immunoassay in 150 HD patients, 90 without DRA and 60 with DRA, before HD. Simple regression analysis was performed to investigate the relationship between serum level of MMP-3 and clinical parameters, including age, HD duration, C-reactive protein and beta2 microglobulin (BMG). RESULTS: Serum levels of MMP-3 were significantly higher in HD patients with DRA than in HD patients without DRA (258.2 +/- 118.1 vs 201.5 +/- 98.4 pg/mL, P = 0.0017), and both levels were significantly higher than those of healthy subjects (45.6 +/- 13.4 pg/mL, P < 0.0001). Serum MMP-3 levels significantly correlated with serum levels of BMG (r = 0.197, P = 0.0164) and HD duration (r = 0.168, P = 0.0427). Moreover, serum MMP-3 levels significantly correlated with serum BMG levels in HD patients without DRA (r = 0.341, P = 0.0012), but not in HD patients with DRA. CONCLUSION: Our results suggest that matrix metalloproteinase activity increases in HD patients, which may be associated with BMG and DRA.
Assuntos
Amiloidose/enzimologia , Falência Renal Crônica/terapia , Metaloproteinase 3 da Matriz/sangue , Diálise Renal/efeitos adversos , Idoso , Amiloidose/etiologia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Feminino , Humanos , Falência Renal Crônica/enzimologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Microglobulina beta-2/sangueRESUMO
The shape of the uroflowmetrogram reflects voiding conditions. Using a voiding simulation, we examined whether the urethral loss coefficient (LC) calculated from the approximated uroflowmetrogram correlates with parameters that regulate the shape of the uroflowmetrogram. A total of 161 normal and abnormal uroflowmetrograms were used. Normal female subjects and patients before and after transurethral resection of the prostate (TURP) were also studied. The ratio of maximum flow rate (Q(max)) to flow time (T), a parameter expressing the shape of the uroflowmetrogram, was calculated. The uroflowmetrograms were approximated using a voiding model, and the urethral LC was calculated. As a result, a strong negative correlation was observed between the Q(max)-flow time ratio, Q(max)/ T, and LC. Q(max)/T is the vertical to horizontal ratio of the uroflowmetrogram and indicates the average degree of acceleration of flow rate during voiding. On the other hand, urethral LC, which can be estimated from the shape of the uroflowmetrogram, is considered a kind of urethral resistance. We concluded that when urethral resistance is high, the degree of acceleration of flow rate is low on average. Our study also indicated that Qmax/T was less affected by voided volume (VV) compared to Q(max). As Q(max)/T is not as dependent on VV, it is useful for comparing cases with different VV.
Assuntos
Uretra/fisiologia , Micção/fisiologia , Urodinâmica/fisiologia , Feminino , Humanos , Masculino , Pressão , Ressecção Transuretral da PróstataRESUMO
The brain is composed of many different types of neurons. Therefore, analysis of brain activity with single-cell resolution could provide fundamental insights into brain mechanisms. However, the electrical signal of an individual neuron is very small, and precise isolation of single neuronal activity from moving subjects is still challenging. To measure single-unit signals in actively behaving states, establishment of technologies that enable fine control of electrode positioning and strict spike sorting is essential. To further apply such a single-cell recording approach to small brain areas in naturally behaving animals in large spaces or during social interaction, we developed a compact wireless recording system with a motorized microdrive. Wireless control of electrode placement facilitates the exploration of single neuronal activity without affecting animal behaviors. Because the system is equipped with a newly developed data-encoding program, the recorded data are readily compressed almost to theoretical limits and securely transmitted to a host computer. Brain activity can thereby be stably monitored in real time and further analyzed using online or offline spike sorting. Our wireless recording approach using a precision motorized microdrive will become a powerful tool for studying brain mechanisms underlying natural or social behaviors.
Assuntos
Comportamento Animal/fisiologia , Neurônios/fisiologia , Tecnologia sem Fio , Animais , Eletrodos Implantados , Eletrofisiologia , RatosRESUMO
BACKGROUND: It has been shown that the transcription factors activator protein (AP)-1 and nuclear factor (NF)-kappaB play a pivotal role in various renal diseases. We aimed to study their activations in chronic cyclosporine A (CsA) nephrotoxicity and evaluate the effect of magnesium (Mg) supplementation and blockade of the renin-angiotensin system (RAS), which are known to ameliorate CsA nephrotoxicity, on these transcription factors. METHODS: CsA (15 mg/kg/day) was administered subcutaneously daily to rats maintained on a low-sodium diet for 7, 14, and 28 days. DNA-binding activities of AP-1 and NF-kappaB in renal cortex were determined by electrophoretic mobility shift assay. RESULTS: DNA-binding activity of AP-1 and NF-kappaB started to increase at day 14 and further elevated at day 28 by CsA treatment. These activations were markedly attenuated when rats were maintained on a high-Mg diet. In contrast, angiotensin-converting enzyme inhibitor (ACEI) had no effect on CsA-induced AP-1 activation. CsA-induced activation of NF-kappaB was suppressed by ACEI at day 14, whereas such effect could not be observed at day 28. CONCLUSIONS: Renal cortical AP-1 and NF-kappaB DNA binding were activated in chronic CsA nephrotoxicity. These activations were induced largely by means of RAS-independent mechanisms. It is suggested that prevention of CsA-induced DNA-binding activation of these transcription factors is at least in part responsible for the beneficial effects of Mg supplementation on CsA nephrotoxicity.
Assuntos
Ciclosporina/intoxicação , Imunossupressores/intoxicação , Magnésio/uso terapêutico , NF-kappa B/metabolismo , Néfrons/efeitos dos fármacos , Néfrons/fisiopatologia , Fator de Transcrição AP-1/metabolismo , Animais , Doença Crônica , Eletroforese , Masculino , Néfrons/patologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Hypomagnesemia is a common finding of cyclosporine (CsA)-treated patients and has been proposed as both a cause and a consequence of CsA-induced nephrotoxicity. This experiment was conducted to elucidate the role of hypomagnesemia in the pathogenesis of chronic CsA nephropathy. METHODS: CsA (15 mg/kg/day subcutaneously) was administered to rats maintained on a low-sodium diet for 1, 2, and 4 weeks, and the effects of magnesium (Mg) supplementation on renal function, renal histology, and renal gene expression profile of fibrogenic molecules and vasoconstrictors was examined. RESULTS: CsA elicited hypomagnesemia and induced a progressive decline in glomerular filtration. At 28 day, renal tubular atrophy and cortical striped interstitial fibrosis were evident with CsA treatment. Dietary supplementation of Mg ameliorated CsA-induced hypomagnesemia and almost completely abolished CsA-induced chronic fibrotic lesions. Neither CsA nor Mg supplementation affected blood pressure. Renal cortical mRNA of transforming growth factor beta, plasminogen activator inhibitor (PAI)-1, and extracellular matrix started to increase at 14 days and elevated further at 28 days. In contrast, the increase in mRNA of tissue inhibitor of matrix metalloproteinase-1 and renin was evident early at 7 days and reached peak at 14 days. These mRNA increases, except that of renin, were almost abolished when hypomagnesemia was corrected. Magnesium supplementation also improved glomerular dysfunction, at least in part, through inhibition of up-regulated mRNA of endothelin-1. CONCLUSION: CsA-induced hypomagnesemia contributes to chronic renal fibrotic lesions seen during CsA treatment through up-regulation of fibrogenic molecules, most notably early activation of tissue inhibitor of matrix metalloproteinase-1 expression.
Assuntos
Ciclosporina/toxicidade , Imunossupressores/toxicidade , Rim/efeitos dos fármacos , Magnésio/sangue , Animais , Northern Blotting , Colágeno/genética , Ciclosporina/sangue , Endotelina-1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Renina/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
BACKGROUND: We have previously shown that correction of hypomagnesemia by magnesium (Mg) supplementation ameliorates chronic cyclosporine A (CsA) nephropathy via inhibiting gene expression of fibrogenic molecules. Experiments were conducted to further elucidate upstream mechanism of the beneficial effects upon CsA nephrotoxicity. METHODS: CsA (15 mg/kg/day, subcutaneous [SC]) was administered daily to rats maintained on low sodium diet for 7, 14, and 28 days. Because blockade of renin-angiotensin system improves chronic CsA nephropathy, the effects of Mg supplementation and those of angiotensin-converting enzyme inhibitor (ACEI) were compared on renal function, renal histology, mononuclear cell infiltration, and gene expression profile. RESULTS: CsA induced a decline in glomerular filtration and developed characteristic striped fibrosis that were mostly evident at day 28. Mg attenuated CsA-induced impaired renal function, whereas ACEI did not. Interstitial inflammation as evidenced by monocyte/macrophage infiltration preceded the renal fibrosis and increased progressively with the CsA treatment period. Concomitantly, CsA markedly up-regulated expression of chemoattractant proteins, osteopontin, and monocyte chemoattractant protein-1. These changes were abolished by Mg but were only partially affected with ACEI. CsA promoted renal mRNA expression of fibrogenic molecules and extracellular matrices that were almost completely abolished by Mg but partially suppressed by ACEI. Similarly, CsA-induced chronic fibrotic lesion was markedly attenuated by Mg supplementation but was partially attenuated by ACEI. CONCLUSION: Mg supplementation abolished CsA-induced precedent interstitial inflammation possibly via inhibition of chemoattractants expression and consequently attenuated tubulointerstitial fibrosis. In this protective mechanism, factors independent of the renin-angiotensin system appears to be mainly involved.
Assuntos
Ciclosporina/toxicidade , Imunossupressores/toxicidade , Rim/efeitos dos fármacos , Magnésio/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Northern Blotting , Quimiocina CCL2/genética , Doença Crônica , Colágeno/genética , Endotelina-1/genética , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Masculino , Osteopontina , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/fisiologia , Sialoglicoproteínas/análise , Sialoglicoproteínas/genética , Inibidor Tecidual de Metaloproteinase-1/genéticaRESUMO
We previously reported that pyrrolidine dithiocarbamate blocked nuclear factor-kappaB (NF-kappaB) activation and attenuated interstitial inflammation and tubulointerstitial fibrosis in the rat obstructive nephropathy. Since pyrrolidine dithiocarbamate is an anti-oxidant and possesses additional biological properties, present experiment was conducted to clarify further the role of NF-kappaB in the development of tubulointerstitial fibrosis in obstructed kidney using a proteasome inhibitor that blocks NF-kappaB through stabilizing IkappaB, an endogenous inhibitor of NF-kappaB. At 5 days following unilateral ureteral obstruction (UUO) in rats, obstructed kidney exhibited tubulointerstitial fibrosis that was associated with macrophage infiltration. UUO decreased renal cortical IkappaB protein contents with concomitant increases in NF-kappaB DNA-binding activity and gene expression of monocyte chemoattractant protein-1. Administration of PSI, N-benzyloxy-carbonyl-Ile-Glu (O-t-Bu)-Ala-leucinal, a proteasome inhibitor, (3 mg/kg/day, s.c., b.i.d) to UUO rats inhibited proteasome activity and attenuated the changes in IkappaB content, NF-kappaB activity and MCP-1 mRNA expression observed in UUO rats. PSI also decreased macrophage influx and attenuated the development of fibrosis. Furthermore, up-regulated gene expression of pro-fibrogenic molecules observed in the obstructed kidney was attenuated by PSI. These results further support the notion that NF-kappaB plays an important role in the development of renal fibrosis in the obstructive nephropathy.
Assuntos
Rim/patologia , Complexos Multienzimáticos/antagonistas & inibidores , NF-kappa B/fisiologia , Animais , Northern Blotting , Western Blotting , Núcleo Celular/metabolismo , Quimiocina CCL2/biossíntese , Quimiocina CCL2/metabolismo , Cisteína Endopeptidases , Citoplasma/metabolismo , DNA/química , DNA/metabolismo , Fibrose , Proteínas I-kappa B/farmacologia , Rim/efeitos dos fármacos , Córtex Renal/patologia , Macrófagos/metabolismo , Monócitos/metabolismo , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma , Ligação Proteica , RNA Mensageiro/metabolismo , Ratos , Fatores de Tempo , Regulação para CimaRESUMO
Oral adsorbent, AST-120 removes uremic toxins (such as indoxyl sulfate) and retards the progression of chronic renal failure (CRF). However, its mechanism of action has not been precisely clarified. Since indoxyl sulfate elicits renal tubular nuclear factor-kappaB (NF-kappaB) activation in vitro, the present experiments were conducted to elucidate the involvement of NF-kappaB in the beneficial effects of AST-120 using rats with 3/4 nephrectomy, a model of early-stage CRF. Daily administration of AST-120 was started at 6 weeks after 3/4 nephrectomy and continued for 18 weeks. Sham-operated rats, untreated CRF rats and AST-120-treated CRF rats were compared for NF-kappaB DNA-binding activity, gene expression and renal histology. Systolic blood pressure was increased in CRF rats, and this increase was not affected by AST-120. Blood urea nitrogen, serum creatinine and urinary protein were increased in CRF rats. Although AST-120 attenuated these increases, it did not do so to a statistically significant extent. Indoxyl sulfate, which was accumulated in serum of CRF rats, was significantly eliminated by AST-120. Renal cortical NF-kappaB DNA-binding activity was increased in CRF rats. AST-120 significantly inhibited this increase. Monocyte/macrophage infiltration and increased monocyte chemoattractant protein-1 (MCP-1) mRNA observed in CRF rats were attenuated by AST-120. Furthermore, AST-120 significantly blocked renal fibrosis with concomitant inhibition of transforming growth factor beta1 (TGF-beta1) gene expression. It appeared that AST-120 reduced NF-kappaB activation and possibly the activity of NF-kappaB-dependent pathways of interstitial inflammation including MCP-1 expression and macrophage infiltration. The anti-inflammatory effect of AST-120 mediated via inhibition of NF-kappaB is a possible mechanism by which AST-120 retards the progression of renal fibrosis in CRF.
Assuntos
Carbono/farmacologia , Falência Renal Crônica/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Óxidos/farmacologia , Animais , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Modelos Animais de Doenças , Ensaio de Desvio de Mobilidade Eletroforética , Fibrose , Imuno-Histoquímica , Córtex Renal/efeitos dos fármacos , Córtex Renal/patologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , RNA Mensageiro/metabolismo , RatosRESUMO
We have developed a microfabricated fluorescence-activated cell sorter system using a thermoreversible gelation polymer (TGP) as a switching valve. The glass sorter chip has Y-shaped microchannels with one inlet and two outlets. A biological specimen containing fluorescently labeled cells is mixed with a solution containing a thermoreversible sol-gel polymer. The mixed solution is then introduced into the sorter chip through the inlet. The sol-gel transformation was locally induced by site-directed infrared laser irradiation to plug one of the outlets. The fluorescently labeled target cells were detected with sensitive fluorescence microscopy. In the absence of a fluorescence signal, the collection channel is plugged through laser irradiation of the TGP and the specimens are directed to the waste channel. Upon detection of a fluorescence signal from the target cells, the laser beam is then used to plug the waste channel, allowing the fluorescent cells to be channeled into the collection reservoir. The response time of the sol-gel transformation was 3 ms, and a flow switching time of 120 ms was achieved. Using this system, we have demonstrated the sorting of fluorescent microspheres and Escherichia coli cells expressing fluorescent proteins. These cells were found to be viable after extraction from the sorting system, indicating no damage to the cells.
Assuntos
Resinas Acrílicas/efeitos da radiação , Citometria de Fluxo/instrumentação , Temperatura Alta , Dispositivos Lab-On-A-Chip , Lasers , Polietilenoglicóis/efeitos da radiação , Ácidos Polimetacrílicos/efeitos da radiação , Resinas Acrílicas/química , Escherichia coli/citologia , Citometria de Fluxo/métodos , Proteínas de Fluorescência Verde/análise , Microscopia de Fluorescência/instrumentação , Microscopia de Fluorescência/métodos , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Sensibilidade e Especificidade , Fatores de TempoRESUMO
BACKGROUND: Chronic tacrolimus (FK506) nephrotoxicity is characterized by renal fibrosis with interstitial inflammation. Since nuclear factor-kappaB (NF-kappaB) plays a key role in chronic inflammatory diseases including renal disease, the present study was conducted to elucidate the role of NF-kappaB in the pathogenesis of chronic FK506-induced nephropathy. METHODS: FK506 (1 mg/kg/day, SC) was administered daily to rats maintained on low sodium diet for 42 days. Some rats were treated with a putative NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC; 100, 200 mg/kg/day, by gavage). The renal function, renal histology, renal NF-kappaB-DNA binding activity and gene expression profile were examined. RESULTS: FK506 caused a decline in glomerular filtration and induced characteristic renal morphologic changes including arteriolopathy, tubular atrophy and interstitial fibrosis. FK506 markedly activated renal cortical NF-kappaB-DNA binding. PDTC administration inhibited NF-kappaB-DNA binding activity in a dose dependent manner. With higher dose, NF-kappaB-DNA binding activity was decreased to a control level. PDTC had little effect on FK506-induced renal dysfunction. Renal cortical monocyte/macrophage infiltration observed in FK506-treated rats was dramatically suppressed by PDTC. FK506 up-regulated renal cortical gene expression of chemoattractant proteins, monocyte chemoattractant protein-1 (MCP-1) and osteopontin. PDTC significantly blocked MCP-1 gene expression but had no effect on osteopontin gene expression. Tubular atrophy and tubulointerstitial fibrosis, but not arteriolopathy, were significantly attenuated by PDTC. FK506 increased renal mRNA expression of fibrogenic molecules and extracellular matrices that also were attenuated by PDTC treatment. CONCLUSIONS: NF-kappaB plays an important role in mediating cortical monocyte/macrophage infiltration and in the pathogenesis of tubular injury and interstitial fibrosis in experimental FK506-induced chronic nephropathy.
Assuntos
Imunossupressores/toxicidade , Nefropatias/prevenção & controle , NF-kappa B/metabolismo , Pirrolidinas/metabolismo , Tacrolimo/toxicidade , Tiocarbamatos/metabolismo , Animais , Quimiocina CCL2/genética , Doença Crônica , Ensaio de Desvio de Mobilidade Eletroforética , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Monócitos/efeitos dos fármacos , Monócitos/patologia , Osteopontina , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Sialoglicoproteínas/genéticaRESUMO
The present study was conducted to elucidate the role of oxidative stress and nuclear factor-kappaB (NF-kappaB) in the beneficial effects of angiotensin receptor blockade on obstructive nephropathy. Unilateral ureteral occlusion in rats elicited tubulo-interstitial fibrosis with concomitant macrophage infiltration and increased expression of monocyte chemoattractant protein-1. These changes were accompanied by an induction of renal cortical lipid peroxidation and activation of NF-kappaB. Both an AT(1) antagonist, candesartan, and a NF-kappaB inhibitor, pyrrolidine dithiocarbamate, markedly attenuated these changes and to a similar extent. These results suggest that the beneficial effects of angiotensin blockade are mediated by the inhibition of oxidative stress and subsequent NF-kappaB activation in obstructive nephropathy.