RESUMO
Objectives: Acute kidney injury (AKI) is a major component of isoproterenol (ISO) induced cardiorenal syndrome. In this study, we investigated the effect of TLR4-IN-C34 as a toll-like receptor (TLR)-4 inhibitor on ameliorating ISO-induced AKI and the possible molecular underlying pathways. Materials and Methods: The study included 4 groups: control group, ISO group (rats received 100 mg/kg ISO in 2 doses 24 hr apart, SC), ISO+C341 and ISO+C343 groups (rats received 1 or 3 mg/kg TLR4-IN-C34 respectively twice one hour before each ISO injection, IP). Results: Obtained results showed that TLR4-IN-C34 injection prior to ISO decreased serum creatinine level (P<0.05). Renal tissue histopathologic changes were markedly decreased by TLR4-IN-C34. Renal relative expression of MAPK and MyD88 mRNA decreased significantly in both ISO+C341 and ISO+C343 groups compared with the ISO group (P<0.05). Furthermore, TLR-IN-C34 lowered the inflammatory cytokines IL-8, IL-1ß, and IL-12 renal levels (P<0.05). Immunostained kidney sections showed a marked decrease in NF-κb positive cells in addition to the apoptotic marker Bax (P<0.05) by the two tested doses of TLR4-IN-C34. On the other hand, the expression of the antiapoptotic marker Bcl-2 by renal cells was markedly increased. Conclusion: It can be concluded that TLR4-IN-C34 ameliorates ISO-induced AKI through anti-inflammatory anti-apoptotic effects and modulation of TLR4 signaling pathways.
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AIMS: Chemical renal toxicity is common and has limited therapeutic interventions. The NLRP3 inhibitor dapansutrile (DAPA) undergoes clinical phase II trials and it shows promising beneficial effects in various inflammatory diseases. The current study aims at evaluating the effect of DAPA on folic acid (FA) induced acute kidney injury (AKI) and its possible transition to chronic injury. MATERIALS AND METHODS: Two treatment protocols were studied depending on DAPA injection timing. A prophylactic protocol involving the injection of DAPA (0.2 mg/kg) daily for seven days before FA challenge and a therapeutic protocol where DAPA was injected after FA. Each protocol included four groups of rats: control group, DAPA group, FA group and DAPA+FA group. Serum creatinine, urea and uric acid were measured. Also, kidney injury, necrosis and fibrosis percentage in addition to infiltration of CD68 positive cells were evaluated. Activation markers of inflammasome and the expression of Ki-67 and LC-3 were measured. KEY FINDINGS: Results showed an improvement in renal tissue integrity and a significant decrease in kidney function biomarkers, caspase-1, IL-1ß and IL-18 by DAPA injection (p < 0.05). In addition, DAPA decreased the proliferation marker Ki-67 and the autophagic marker LC-3 (p < 0.01). SIGNIFICANCE: DAPA potentially alleviates FA induced nephrotoxicity through targeting inflammasome/caspase-1/IL axis. Moreover, it shows a regulatory effect on renal regeneration and autophagy.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Caspase 1/metabolismo , Ácido Fólico/toxicidade , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Nitrilas/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Animais , Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Biomarcadores , Proliferação de Células , Interleucina-18/antagonistas & inibidores , Interleucina-18/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Antígeno Ki-67/metabolismo , Rim/efeitos dos fármacos , Masculino , Nitrilas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The therapeutic use of numerous pharmacological agents may be limited due to their nephrotoxicity and associated kidney injury. The aim of our study is to test the hypothesis that the blockade of tyrosine kinase-linked receptors signaling protects against chemically induced nephrotoxicity. To test our hypothesis, we investigated sunitinib as an inhibitor for tyrosine kinase signaling for both vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR) against adenine-induced nephrotoxicity. Four groups of adult male Swiss albino mice were investigated: normal group, adenine group, sunitinib group, and the adenine+sunitinib group that received concurrent administration for both adenine and sunitinib. Kidney function and oxidative stress biomarkers were analyzed. Tubular injury and histopathological changes were examined. Renal expression of B-cell lymphoma-2 (Bcl-2), the tumor suppressor p53, transforming growth factor beta-1 (TGF-ß1), phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phospho-signal transducer and activator of transcription (phospho-STAT3) were measured. The results obtained showed significant improvement (p < 0.05) in kidney function and antioxidant biomarkers in the adenine+sunitinib group. Kidney fibrosis and tubular injury scores were significantly (p < 0.05) less in the adenine+sunitinib group and that of p53 expression as well. Furthermore, sunitinib decreased (p < 0.5) renal levels of TGF-ß1, p-ERK1/2, and phospho-STAT3 while elevating Bcl-2 expression score. In conclusion, sunitinib diminished adenine-induced nephrotoxicity through interfering with profibrogenic pathways, activating anti-apoptotic mechanisms, and possessing potential antioxidant capabilities.
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Renal fibrosis is a failed regenerative process that facilitates chronic kidney disease progression. The current study was designed to study the effect of erlotinib, a receptor tyrosine kinase inhibitor, on the progression of renal fibrosis. The study included four groups of mice: control group; adenine group: received adenine (0.2% w/w) daily with food for 4 weeks; erlotinib group: received 80 mg/kg/day erlotinib orally (6 ml/kg/day, 1.3% w/v suspension in normal saline 0.9%) for 4 weeks; adenine + erlotinib group: received adenine and erlotinib concurrently. Kidney function and antioxidant biomarkers were measured. Renal expression of Bcl2 and p53 and histopathological changes (tubular injury and renal fibrosis) were scored. Renal tissue levels of transforming growth factor-ß1, p-ERK1/2 and p-STAT3 were measured. Results obtained showed significant decrease (P < 0.001) in serum creatinine, urea and uric acid in erlotinib + adenine group. Level of malondialdehyde was decreased significantly (P < 0.001) while reduced glutathione and catalase levels were increased (P < 0.01) by erlotinib concurrent administration. Erlotinib markedly reduced fibrosis and tubular injury and decreased TGF-ß1, p-ERK1/2 and p-STAT3 (P < 0.5). In addition, expression level of Bcl-2 was elevated (P < 0.001) while that of p53-was reduced compared to adenine alone. Erlotinib can attenuate renal fibrosis development and progression through anti-fibrotic, antioxidant and anti-apoptotic pathways.
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Fibrose/tratamento farmacológico , Nefropatias/tratamento farmacológico , Fator de Transcrição STAT3/genética , Fator de Crescimento Transformador beta1/genética , Proteína Supressora de Tumor p53/genética , Adenina/toxicidade , Animais , Modelos Animais de Doenças , Fibrose/induzido quimicamente , Fibrose/genética , Fibrose/patologia , Humanos , Rim/efeitos dos fármacos , Nefropatias/induzido quimicamente , Nefropatias/genética , Nefropatias/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/genética , Insuficiência Renal/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Modified citrus pectin (MCP) is a pH modified form of the dietary soluble citrus peel fiber known as pectin. The current study aims at testing its effect on liver fibrosis progression. Rats were injected with CCl4 (1 mL/kg, 40% v/v, i.p., twice a week for 8 weeks). Concurrently, MCP (400 or 1200 mg/kg) was administered daily in drinking water from the first week in groups I and II (prophylactic model) and in the beginning of week 5 in groups III and IV (therapeutic model). Liver function biomarkers (ATL, AST, and ALP), fibrosis markers (laminin and hyaluronic acid), and antioxidant biomarkers (reduced glutathione (GSH) and superoxide dismutase (SOD)) were measured. Stained liver sections were scored for fibrosis and necroinflammation. Additionally, expression of galectin-3 (Gal-3), α-smooth muscle actin (SMA), tissue inhibitor metalloproteinase (TIMP)-1, collagen (Col)1A1, caspase (Cas)-3, and apoptosis related factor (FAS) were assigned. Modified pectin late administration significantly (p < 0.05) decreased malondialdehyde (MDA), TIMP-1, Col1A1, α-SMA, and Gal-3 levels and increased levels of FAS, Cas-3, GSH, and SOD. It also decreased percentage of fibrosis and necroinflammation significantly (p < 0.05). It can be concluded that MCP can attenuate liver fibrosis through an antioxidant effect, inhibition of Gal-3 mediated hepatic stellate cells activation, and induction of apoptosis.
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Apoptose , Citrus/química , Fibras na Dieta/uso terapêutico , Galectina 3/antagonistas & inibidores , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/prevenção & controle , Pectinas/uso terapêutico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Antioxidantes/química , Antioxidantes/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Tetracloreto de Carbono , Fibras na Dieta/administração & dosagem , Fibras na Dieta/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Progressão da Doença , Frutas/química , Galectina 3/metabolismo , Células Estreladas do Fígado/patologia , Temperatura Alta , Concentração de Íons de Hidrogênio , Peroxidação de Lipídeos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática Experimental/dietoterapia , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/fisiopatologia , Masculino , Estresse Oxidativo , Pectinas/administração & dosagem , Pectinas/efeitos adversos , Pectinas/química , Ratos Sprague-Dawley , SolubilidadeRESUMO
BACKGROUND: Heat shock protein 90 (Hsp90) is proposed to be involved in liver disorders. This study was conducted to test effect of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90, on attenuating thioacetamide induced liver fibrosis in vivo. METHODS: Four groups of Swiss albino male mice (CD-1 strain) were used as follows: control group; thioacetamide group (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks); thioacetamide plus 17-AAG groups (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks plus 25 or 50mg/kg 17-AAG, ip injection, 5 days/week along the last 4 weeks). Fibrosis was quantified by measuring hydroxyproline level and by morphometry and oxidative stress biomarkers were assigned. Relative hepatic mRNA expressions of α-smooth muscle actin (α-SMA), collagen-1-alpha-1 (Col1A1) and tissue inhibitor metalloproteinase-1 (TIMP-1) mRNAs were measured by RT-PCR. Levels of the apoptotic markers caspase-3, factor related apoptosis (Fas) and Hsp-90 were assigned in tissue homogenate. RESULTS: 17-AAG (50mg/kg) significantly decreased fibrosis percentage significantly (p<0.001, 0.05) compared to thioaceatmide and 25mg/kg, respectively. Malondialdehyde, Hsp90, α-SMA, Col1A1 and TIMP-1 expression levels were significantly reduced (p<0.05) by the inhibitor large dose. Levels of GSH, caspase-3 and Fas were markedly (p<0.001) increased in the group received 17-AAG (50mg/kg) compared to other groups. CONCLUSION: The Hsp90 inhibitor, 17-AAG, can attenuate thioacetamide hepatotoxicity through oxidative stress counterbalance, reducing stellate cells activity and inducing apoptosis.
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Benzoquinonas/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Tioacetamida/farmacologia , Actinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Receptor fas/metabolismoRESUMO
Probiotics and antioxidants have a definite improving effect in cardiovascular diseases. This study aims at mitigating doxorubicin toxicity on cardiac function through consuming a functional food. Five groups of adult male Sprague-Dawley rats were used along 22 weeks. Group I received 30 g/kg/day food enriched with yogurt, green tea extract, and carrots (80, 0.84, and 100 g/kg diet, respectively) from the first week, group II received carvedilol 30 mg/kg/day orally from week 17, group III received both carvedilol and tested food, and groups IV and V were +ve and -ve control groups, respectively. In week 17, cardiomyopathy was induced by i.p. injection of 2.5 mg/kg doxorubicin every 48 h for 2 weeks. Histopathological and electrophysiological examinations and biochemical analysis were done. Lipid peroxidation, antioxidant effect, heart failure compensatory mediators, and proinflammatory cytokines were assessed. Tested food normalized time between the start of Q wave and the end of T wave on electrocardiogram (QT interval) and heart rate compared to the doxorubicin group (P<.05). It also improved hypertrophy indicated by a significant (P<.05) decrease in heart/body weight ratio, angiotensin-II (Ang-II), and atrial natriuretic peptide (ANP) serum levels. Histopathological examination of cardiac sections from the tested food group revealed less marked vacuolization and low perivascular fibrosis percentage (0.7803 ± 0.04). A significant (P<.001) decrease in serum creatine kinase-membrane bound, lactate dehydrogenase, triglycerides, cholesterol, low-density lipoprotein cholesterol, and tissue malondialdehyde (MDA) levels was observed in addition to an increase in serum Na(+)/K(+) ATP1A1 and cardiac reduced glutathione (GSH) levels. Tested food also lowered the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) serum levels significantly (P<.01). Probiotic food containing Lactobacillus acidophilus, green tea, and carrots can improve membrane integrity and cardiac contractility in doxorubicin-induced cardiomyopathy by decreasing TNF-α, IL-6, MDA, increasing GSH, and modulating compensatory mediators such as Ang-II and ANP.
Assuntos
Antioxidantes/uso terapêutico , Cardiomiopatias/prevenção & controle , Alimento Funcional , Coração/efeitos dos fármacos , Lactobacillus acidophilus , Miocárdio , Iogurte/microbiologia , Angiotensina II/sangue , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Fator Natriurético Atrial/sangue , Camellia sinensis/química , Carbazóis/farmacologia , Cardiomiopatias/sangue , Cardiomiopatias/induzido quimicamente , Cardiotônicos/uso terapêutico , Carvedilol , Colesterol/sangue , Citocinas/sangue , Daucus carota/química , Doxorrubicina/efeitos adversos , Coração/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/sangue , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Probióticos/uso terapêutico , Propanolaminas/farmacologia , Ratos Sprague-DawleyRESUMO
The tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl4 for 12 weeks. During the last 8 weeks of treatment, rats were also injected daily intraperitoneally with 20 mg/kg imatinib or 20, 10 or 5 mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti-inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of α-smooth muscle actin, transforming growth factor (TGF)-ß1 antibodies and platelet-derived growth factor receptor ß (PDGFRß) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10 mg/kg) significantly (P < 0.05) decreased all serum fibrotic markers measured, but 20 mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P < 0.05) decreased the CCl4 -induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10 mg/kg nilotinib significantly decreased TGF-ß1 levels and tissue expression of its antibody, as well expression of PDGFRß. In conclusion, low doses (5 and 10 but not 20 mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)-1 and IL-6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF-ß1 levels and decreasing expression of PDGFRß.