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1.
Korean J Intern Med ; 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32942841

RESUMO

Background/Aims: Accumulating evidence indicates that L-carnitine (LC) protects against multiorgan damage through its antioxidant properties and preservation of the mitochondria. Little information is available about the effects of LC on renal fibrosis. This study examined whether LC treatment would provide renoprotection in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Methods: Sprague-Dawley rats that underwent UUO were treated daily with LC for 7 or 14 days. The influence of LC on renal injury caused by UUO was evaluated by histopathology, and analysis of gene expression, oxidative stress, mitochondrial function, programmed cell death, and phosphatidylinositol 3-kinase (PI3K)/ AKT/forkhead box protein O 1a (FoxO1a) signaling. In addition, H2O2-exposed human kidney cells (HK-2) were treated with LC. Results: LC treatment inhibited expression of proinflammatory and profibrotic cytokines, and was followed by a significant attenuation of tubulointerstitial inflammation and fibrosis. The increased oxidative stress caused by UUO was associated with mitochondrial dysfunction and excessive apoptosis and autophagy via PI3K/AKT/FoxO1a-dependent signaling, and this was abrogated by administration of LC. In H2O2-exposed HK-2 cells, LC decreased intracellular production of reactive oxygen species, and suppressed expression of profibrotic cytokines and reduced the number of apoptotic cells. Conclusions: LC protects against the progression of tubulointerstitial fibrosis in an obstructed kidney.

2.
Acta Pharmacol Sin ; 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555441

RESUMO

Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy. L-carnitine (LC) has been shown to protect against various types of renal injury. In this study, we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus (TAC) nephropathy. SD rats were injected with TAC (1.5 mg · kg-1 · d-1, sc) for 4 weeks. Renoprotective effects of LC were assessed in terms of renal function, histopathology, oxidative stress, expression of inflammatory and fibrotic cytokines, programmed cell death (pyroptosis, apoptosis, and autophagy), mitochondrial function, and PI3K/AKT/PTEN signaling. Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy. At a molecular level, TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney, induced oxidative stress, and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN. Coadministration of LC (200 mg · kg-1 · d-1, ip) caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats. Furthermore, LC exerted anti-inflammatory and antioxidant effects, prevented mitochondrial dysfunction, and modulated the expression of a series of apoptosis- and autophagy-controlling genes to promote cell survival. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TAC (50 µg/mL) in vitro, which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death (pyroptosis, apoptosis, and autophagy) through interfering with PI3K/AKT/PTEN signaling. The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002 (25 µM). In conclusion, LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.

3.
Acta Pharmacol Sin ; 41(12): 1597-1608, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32300244

RESUMO

Tissue kallikrein has protective function against various types of injury. In this study, we investigated whether exogenous pancreatic kininogenase (PK) conferred renoprotection in a rat model of unilateral ureteral obstruction (UUO) and H2O2-treated HK-2 cells in vitro. SD rats were subjected to UUO surgery, then PK (7.2 U/g per day, ip) was administered for 7 or 14 days. After the treatment, rats were euthanized; the obstructed kidneys were harvested for further examination. We found that PK administration significantly attenuated interstitial inflammation and fibrosis, and downregulated the expression of proinflammatory (MCP-1, TLR-2, and OPN) and profibrotic (TGF-ß1 and CTGF) cytokines in obstructed kidney. UUO-induced oxidative stress, closely associated with excessive apoptotic cell death and autophagy via PI3K/AKT/FoxO1a signaling, which were abolished by PK administration. We further showed that PK administration increased the expression of bradykinin receptors 1 and 2 (B1R and B2R) mRNA and the production of NO and cAMP in kidney tissues. Coadministration with either B1R antagonist (des-Arg9-[Leu8]-bradykinin) or B2R antagonist (icatibant) abrogated the renoprotective effects of PK, and reduced the levels of NO and cAMP in obstructed kidney. In H2O2-treated HK-2 cells, addition of PK (6 pg/mL) significantly decreased ROS production, regulated the expression of oxidant and antioxidant enzymes, suppressed the expression of TGF-ß1 and MCP-1, and inhibited cell apoptosis. Our data demonstrate that PK treatment protects against the progression of renal fibrosis in obstructed kidneys.

4.
Korean J Intern Med ; 34(5): 1078-1090, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29432674

RESUMO

BACKGROUND/AIMS: Evidence suggests that Shen-Kang (SK), a traditional Chinese herbal medicine, protects against various types of renal injury. In this study, we evaluated whether SK treatment confers renoprotection in a rat model of chronic tacrolimus (TAC) nephropathy. METHODS: Rats were treated daily with TAC (1.5mg/kg, subcutaneously) and SK (450 mg/kg, intravenously) for 4 weeks. The effects of SK on TAC-induced renal injury were assessed by measuring renal function, urine albumin excretion, histopathology, inflammatory cell infiltration, expression of profibrotic (transforming growth factor ß1 [TGF-ß1] and TGF-ß inducible gene-h3 [ßig-h3]) and proinflammatory cytokines, oxidative stress, and apoptotic cell death. RESULTS: Administration of SK preserved glomerular integrity (fractional mesangial area and Wilms tumor 1-positive glomeruli), attenuated tubulointerstitial fibrosis, and reduced the number of ectodermal dysplasia 1-positive cells, and this was paralleled by improved urine albumin excretion and renal dysfunction. At the molecular level, SK treatment suppressed expression of TGF-ß1/Smad2/3, ßig-h3, and proinflammatory cytokines. Oxidative stress and apoptotic cell death were significantly decreased with SK treatment, and apoptosis-related genes were regulated toward cell survival (active caspase-3 and the B-cell lymphoma-2/Bcl2-associated X [Bcl-2/Bax] ratio). CONCLUSION: SK protects against TAC-induced renal injury.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Tacrolimo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Citocinas/metabolismo , Citoproteção , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/metabolismo , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
5.
BMC Nephrol ; 19(1): 63, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29540150

RESUMO

BACKGROUND: Accumulating evidence suggests that a decrease in brain-derived neurotrophic factor (BDNF) level induces a variety of psychiatric and neurological disorders. However, the expression and role of BDNF in the kidney have not been explored. The present study examined the expression of BDNF and tropomyosin-related kinase (Trk) receptors in an experimental model of chronic cyclosporine A (CsA) nephropathy. METHODS: Sprague-Dawley rats on a salt-deplete diet were treated daily for four weeks with vehicle or CsA. Urine profiles, apoptotic cell death, oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-OHdG), and expression of BDNF and Trk receptors (TrkB and TrkC) were compared between groups. The impact of vasopressin infusion on the urine-concentrating ability was examined by measuring the expression of aquaporin-2 (AQP-2) and BDNF and urine profiles in normal and CsA-treated rats. RESULTS: Compared with the vehicle-treated rats, rats given CsA had enhanced urine volume and declined urine osmolality. Immunohistochemistry and immunoblotting showed that BDNF and Trk receptors were constitutively expressed in kidneys from vehicle-treated rats. This was confirmed by double immunofluorescent staining for Na-K-ATPase-α1, AQP-1, and AQP-2. By contrast, the expression of these factors decreased in kidneys from CsA-treated rats (BDNF: 51.1 ± 19.5% vs. 102.0 ± 30.3%, p < 0.01). Downregulation of BDNF was accompanied by impairment of urine osmolality, and this was reversed by exogenous infusion of vasopressin. Notably, the number of TUNEL-positive cells correlated negatively with BDNF expression and positively with urinary 8-OHdG excretion. CONCLUSIONS: BDNF is expressed in the collecting duct of the kidney and may be associated with urine-concentrating ability in an experimental model of chronic CsA-induced nephropathy. Our study provides a new avenue for further investigation of chronic CsA nephropathy.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Ciclosporina/toxicidade , Imunossupressores/toxicidade , Rim/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Expressão Gênica , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
6.
PLoS One ; 9(6): e100798, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24959755

RESUMO

BACKGROUND: Tacrolimus (TAC)-induced pancreatic islet injury is one of the important causes of new-onset diabetes in transplant recipients. This study was performed to evaluate whether a dipeptidyl peptidase IV (DPP IV) inhibitor is effective in improving TAC-induced diabetes mellitus by reducing pancreatic islet injury. METHODS: Rats were treated with TAC (1.5 mg/kg, subcutaneously) and the DPP IV inhibitor MK-0626 (10 or 20 mg/kg, oral gavage) for 4 weeks. The effect of MK-0626 on TAC-induced diabetes was evaluated by assessing pancreatic islet function, histopathology. TAC-induced incretin dysfunction was also examined based on active glucagon-like peptide-1 (GLP-1) levels in the serum after glucose loading. The protective effect of MK-0626 was evaluated by measuring markers of oxidative stress, oxidative resistance, and apoptosis. To determine whether enhanced GLP-1 signaling is associated with these protective effects, we measured the expression of the GLP-1 receptor (GLP-1R) and the effect of the GLP-1 analog exendin-4 on cell viability and oxidative stress in isolated islets. RESULTS: MK-0626 treatment attenuated TAC-induced pancreatic islet dysfunction and islet morphology. TAC treatment led to a defect in active GLP-1 secretion; however, MK-0626 reversed these effects. TAC treatment increased the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), the number of apoptotic death, and the level of active caspase-3, and decreased the level of manganese superoxide dismutase and heme oxygenase-1; MK-0626 treatment reversed these changes. MK-0626 treatment restored the expression of GLP-1R, and direct administration of exendin-4 to isolated islets reduced TAC-induced cell death and 8-OHdG expression. CONCLUSIONS: The DPP IV inhibitor MK-0626 was an effective antidiabetic agent that exerted antioxidative and antiapoptotic effects via enhanced GLP-1 signaling in TAC-induced diabetics.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Tacrolimo/efeitos adversos , 8-Hidroxi-2'-Desoxiguanosina , Animais , Dano ao DNA/efeitos dos fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Desoxiguanosina/urina , Diabetes Mellitus Experimental , Ilhotas Pancreáticas/patologia , Masculino , Ratos , Ratos Sprague-Dawley
7.
Transplantation ; 98(1): 22-8, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24825522

RESUMO

BACKGROUND: Drug-drug interaction between everolimus (EVR) and tacrolimus (TAC) is still undetermined. We evaluated whether EVR enhances TAC-induced organ injury through drug-drug interaction. METHODS: Tacrolimus (6 mg/kg) was given to rats with or without EVR (1 or 2 mg/kg) orally for 4 weeks. The influences of EVR on TAC-induced organ injury were evaluated in terms of nephrotoxicity and pancreatic islet dysfunction. Drug-drug interaction was evaluated by measuring the level of each drug in the blood and target tissue, and the correlation between the two drugs was observed in the blood and target tissue. The concentration of 8-hydroxy-2'-deoxyguanosine in blood or urine was measured as a marker of oxidative stress, and correlation between drug levels and oxidative stress was also evaluated. RESULTS: Tacrolimus treatment alone did not cause overt renal or pancreatic islet injury, but the addition of EVR significantly enhanced the TAC-induced organ injury, as demonstrated by aggravated nephrotoxicity and pancreatic islet dysfunction. The combination of EVR and TAC significantly increased each drug level in the target tissues as well as in blood, and there was good correlation between the two drugs in blood and target organs. The serum and urinary levels of 8-hydroxy-2'-deoxyguanosine were significantly increased in the TAC+EVR group compared with the TAC- or EVR-alone group and were well correlated with drug levels in blood and tissues. CONCLUSIONS: Everolimus enhances TAC-induced target organ injury by increasing oxidative stress via pharmacological interaction in blood and target tissue. This finding provides a better understanding of the effects of EVR when used in combination with TAC.


Assuntos
Imunossupressores/toxicidade , Ilhotas Pancreáticas/efeitos dos fármacos , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sirolimo/análogos & derivados , Tacrolimo/toxicidade , 8-Hidroxi-2'-Desoxiguanosina , Animais , Biomarcadores/sangue , Biomarcadores/urina , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Desoxiguanosina/urina , Interações Medicamentosas , Quimioterapia Combinada , Everolimo , Imunossupressores/sangue , Imunossupressores/farmacocinética , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Rim/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Sirolimo/sangue , Sirolimo/farmacocinética , Sirolimo/toxicidade , Tacrolimo/sangue , Tacrolimo/farmacocinética
8.
Nephron Exp Nephrol ; 126(3): 148-56, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24855017

RESUMO

BACKGROUND: Leflunomide (LEF) and benazepril have renoprotective effects on diabetic nephropathy (DN) through their anti-inflammatory and anti-fibrotic activities. This study investigated whether combined treatment using LEF and benazepril affords superior protection compared with the respective monotherapies. METHODS: Diabetes was induced with streptozotocin (STZ, 65 mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 12 weeks with LEF (10 mg/kg), benazepril (10 mg/kg), or a combination of both. Basic parameters (body weight, fasting blood glucose level, and 24 h urinary protein excretion), histopathology, inflammatory [inflammatory cell infiltration (ED-1), monocyte chemoattractant protein-1 (MCP-1), and Toll-like receptor-2 (TLR-2)] and glomerulosclerotic factors [transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF)], and oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-OHdG) were studied. RESULTS: Benazepril or LEF treatment significantly prevented body weight loss and 24 h urinary protein excretion induced by diabetes; combined treatment with LEF and benazepril further improved these parameters compared with giving each drug alone (all p < 0.01). Increased expression of inflammatory (MCP-1 and TLR-2) and glomerulosclerotic (TGF-ß1 and CTGF) factors in diabetic rat kidney was reduced by treatment with either LEF or benazepril and was further reduced by the combined administration of the two drugs (p < 0.01). These effects were accompanied by suppression of urinary 8-OHdG excretion. There was no significant between-group difference in blood glucose level. CONCLUSIONS: LEF treatment lessens DN, and combined treatment with LEF and benazepril provides synergistic effects in preventing DN.


Assuntos
Benzazepinas/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Isoxazóis/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antifibrinolíticos/administração & dosagem , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Sinergismo Farmacológico , Leflunomida , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento
9.
Nephrology (Carlton) ; 19(8): 490-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24796922

RESUMO

AIMS: Chronic cyclosporine (CsA) treatment induces autophagic cell death characterized by excessive autophagosome formation and decreased autophagic clearance. In this study, we evaluated the influence of ginseng treatment on autophagy in chronic CsA nephropathy. METHODS: Mice were treated with CsA (30 mg/kg) with or without Korean red ginseng (KRG) extract (0.2, 0.4 g/kg) for 4 weeks. The effect of KRG on CsA-induced autophagosome formation was measured using phospholipid-conjugated form of LC3-II, beclin-1, and autophagic vacuoles were visualized with electron microscopy. Autophagic clearance was evaluated by accumulation of p62/sequestosome 1 (p62) and ubiquitin, then double immunolabeling for p62 and either LC3-II or ubiquitin. To demonstrate the association between the effects of KRG treatment on autophagy and apoptosis, double immunolabelling for LC3-II and active caspase-3 was performed. Multiple autophagy pathways were also examined. RESULTS: KRG co-treatment significantly decreased the expression of LC3-II, beclin-1, and the number of autophagic vacuoles compared with the CsA group, and these changes were accompanied by improvements in renal dysfunction and fibrosis. CsA-induced accumulation of p62 and ubiquitin was also decreased by KRG treatment, and these proteins were colocalized with LC3-II and with each other. KRG treatment simultaneously reduced the expression of both active caspase-3 and LC3-II in the injured area. KRG treatment during chronic CsA nephropathy induced the expression of AKT/mTOR, which is a pathway that inhibits autophagy, and reduced AMPK expression. CONCLUSION: Ginseng treatment attenuated CsA-induced excessive autophagosome formation and autophagic aggregates. These findings suggest that ginseng has a renoprotective effect against CsA-induced autophagic cell death.


Assuntos
Autofagia/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Nefropatias/prevenção & controle , Panax , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Doença Crônica , Ciclosporina/efeitos adversos , Nefropatias/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos ICR
10.
PLoS One ; 8(8): e72685, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24009697

RESUMO

BACKGROUND: This study was performed to investigate whether ginseng has a protective effect in an experimental mouse model of cyclosporine-induced pancreatic injury. METHODS: Mice were treated with cyclosporine (30 mg/kg/day, subcutaneously) and Korean red ginseng extract (0.2 or 0.4 g/kg/day, oral gavage) for 4 weeks while on a 0.01% salt diet. The effect of ginseng on cyclosporine-induced pancreatic islet dysfunction was investigated by an intraperitoneal glucose tolerance test and measurements of serum insulin level, ß cell area, macrophage infiltration, and apoptosis. Using an in vitro model, we further examined the effect of ginseng on a cyclosporine-treated insulin-secreting cell line. Oxidative stress was measured by the concentration of 8-hydroxy-2'-deoxyguanosine in serum, tissue sections, and culture media. RESULTS: Four weeks of cyclosporine treatment increased blood glucose levels and decreased insulin levels, but cotreatment with ginseng ameliorated the cyclosporine-induced glucose intolerance and hyperglycemia. Pancreatic ß cell area was also greater with ginseng cotreatment compared with cyclosporine monotherapy. The production of proinflammatory molecules, such as induced nitric oxide synthase and cytokines, and the level of apoptotic cell death also decreased in pancreatic ß cell with ginseng treatment. Consistent with the in vivo results, the in vitro study showed that the addition of ginseng protected against cyclosporine-induced cytotoxicity, inflammation, and apoptotic cell death. These in vivo and in vitro changes were accompanied by decreases in the levels of 8-hydroxy-2'-deoxyguanosine in pancreatic ß cell in tissue section, serum, and culture media during cotreatment of ginseng with cyclosporine. CONCLUSIONS: The results of our in vivo and in vitro studies demonstrate that ginseng has a protective effect against cyclosporine-induced pancreatic ß cell injury via reducing oxidative stress.


Assuntos
Panax/química , Pancreatopatias/tratamento farmacológico , Pancreatopatias/metabolismo , Extratos Vegetais/administração & dosagem , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Ciclosporina/efeitos adversos , Modelos Animais de Doenças , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Testes de Função Renal , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Nitritos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/fisiopatologia , Pancreatopatias/induzido quimicamente
11.
Transplantation ; 96(2): 146-53, 2013 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-23765110

RESUMO

BACKGROUND: Cyclosporine A (CsA)-associated oxidative stress has been proposed as an important mechanism of renal injury. This study was designed to examine whether N-acetylcysteine (NAC), a well-known antioxidant, affects Klotho, antiaging gene, expression and its signaling pathway in an experimental model of chronic CsA nephropathy. METHODS: Mice maintained on a low-sodium diet were given vehicle (olive oil, 1 mL/kg/day), CsA (30 mg/kg/day), NAC (150 mg/kg/day), or a combination of CsA and NAC for 4 weeks. The effect of NAC on CsA-induced renal injury was evaluated with basic parameters, histopathology, and markers of oxidative stress [8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion and manganese superoxide dismutase (MnSOD) expression]. The influence of NAC on Klotho and its signal pathway (p-AKT and p-FoxO1) in CsA-treated mouse kidney was evaluated with immunohistochemistry and/or immunoblot. RESULTS: Concomitant administration of CsA and NAC significantly improved renal function and attenuated tubulointerstitial fibrosis, and these changes were accompanied by decreased urinary 8-OHdG level and increased MnSOD expression. NAC treatment preserved Klotho gene expression compared with CsA treatment alone (P < 0.05), and this correlated with urinary 8-OHdG excretion (r = -0.934) and MnSOD expression (r = 0.873, P < 0.001 for both). Concomitant treatment of CsA and NAC translocated FoxO1 from the cytoplasm to the nucleus, implicating dephosphorylation of FoxO1 by NAC in p-AKT/p-FoxO1 pathway. CONCLUSION: NAC treatment preserves Klotho expression and modifies p-AKT/p-FoxO1 pathway in chronic CsA nephropathy.


Assuntos
Acetilcisteína/farmacologia , Ciclosporina/efeitos adversos , Glucuronidase/genética , Glucuronidase/metabolismo , Imunossupressores/efeitos adversos , Nefropatias/prevenção & controle , 8-Hidroxi-2'-Desoxiguanosina , Acetilcisteína/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Doença Crônica , Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Modelos Animais de Doenças , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica/efeitos dos fármacos , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
12.
Am J Nephrol ; 37(5): 421-33, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23594788

RESUMO

BACKGROUND: This study was performed to investigate whether ginseng extract has a protective effect in an experimental mouse model of chronic cyclosporine (CsA) nephropathy. METHODS: Mice were treated with CsA (30 mg/kg/day, subcutaneously) with or without Korean red ginseng extract (KRG) (0.2, 0.4 g/kg/day, orally) on a 0.01% salt diet for 4 weeks. The effect of KRG on CsA-induced renal injury was evaluated by assessing renal function and pathology, mediators of inflammation, tubulointerstitial fibrosis and apoptotic cell death. Using an in vitro model, we also examined the effect of KRG on CsA-treated proximal tubular cells (HK-2). Oxidative stress was measured by assessing 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in 24-hour urine, tissue sections, and culture media. RESULTS: Four weeks of CsA treatment caused renal dysfunction, typical pathologic lesions and apoptotic cell death. KRG treatment reduced serum creatinine and blood urea nitrogen and histopathology and increased creatinine clearance. Proinflammatory and profibrotic molecules such as induced nitric oxide synthase, cytokines, transforming growth factor (TGF)-ß1 and TGF-ß1-inducible gene h3 and apoptotic cell death, also decreased with KRG treatment. Consistent with these results, in vitro studies showed that addition of KRG protected against CsA-induced morphological changes, cytotoxicity, inflammation, and apoptotic cell death as demonstrated by annexin V binding. These changes were accompanied by decrease in the level of 8-OHdG in urine and culture supernatant after KRG treatment. CONCLUSION: The results of our in vivo and in vitro studies demonstrate that KRG has a protective effect in CsA-induced renal injury via reducing oxidative stress.


Assuntos
Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Nefropatias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Panax , Extratos Vegetais/uso terapêutico , Animais , Biomarcadores/metabolismo , Linhagem Celular , Interações Ervas-Drogas , Humanos , Nefropatias/induzido quimicamente , Nefropatias/patologia , Masculino , Camundongos , Fitoterapia , Extratos Vegetais/farmacologia , Distribuição Aleatória
13.
PLoS One ; 8(3): e59693, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23555748

RESUMO

The aim of this study was to investigate whether hATMSCs protect against cyclosporine (CsA)-induced renal injury. CsA (7.5 mg/kg) and hATMSCs (3×10(6)/5 mL) were administered alone and together to rats for 4 weeks. The effect of hATMSCs on CsA-induced renal injury was evaluated by assessing renal function, interstitial fibrosis, infiltration of inflammatory cells, and apoptotic cell death. Four weeks of CsA-treatment produced typical chronic CsA-nephropathy. Combined treatment with CsA and hATMSCs did not prevent these effects and showed a trend toward further renal deterioration. To evaluate why hATMSCs aggravated CsA-induced renal injury, we measured oxidative stress, a major mechanism of CsA-induced renal injury. Both urine and serum 8-hydroxydeoxyguanosine(8-OHdG) levels were higher in the CsA+hATMSCs group than in the CsA group (P<0.05). An in vitro study showed similar results. Although the rate of apoptosis did not differ significantly between HK-2 cells cultured in hATMSCs-conditioned medium and those cultured in DMEM, addition of CsA resulted in greater apoptosis in HK-2 cells cultured in hATMSCs-conditioned medium. Addition of CsA increased oxidative stress in the hATMSCs-conditioned medium. The results of our study suggest that treatment with hATMSCs may aggravate CsA-induced renal injury because hATMSCs cause oxidative stress in the presence of CsA.


Assuntos
Tecido Adiposo/citologia , Ciclosporina/efeitos adversos , Rim/efeitos dos fármacos , Rim/metabolismo , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/citologia , Estresse Oxidativo/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Meios de Cultivo Condicionados , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Desoxiguanosina/urina , Fibrose , Humanos , Rim/patologia , Rim/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
14.
Nephron Exp Nephrol ; 120(4): e123-33, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22986347

RESUMO

BACKGROUND: We recently reported that long-term cyclosporine (CsA)-induced oxidative stress is associated with decreased expression of klotho, an anti-aging gene. This study evaluated whether the antioxidant effect of statin might upregulate klotho expression in CsA-induced renal injury. METHODS: Two separate experiments were performed. First, the dose-dependent effect of statin on klotho expression was evaluated in normal mouse kidneys. Second, the effect of statin on klotho expression was evaluated in experimental chronic CsA nephropathy in mice. We performed immunohistochemistry and immunoblotting for klotho, Forkhead box O transcription factors [FoxOs; phosphorylated FoxO1 (p-FoxO1) and FoxO3a (p-FoxO3a)] and their target molecules, manganese superoxide dismutase (MnSOD), Bim and hemeoxygenase-1. RESULTS: Statin treatment upregulated klotho expression in a dose-dependent manner in the normal mouse kidney and alleviated the decrease in klotho expression in kidneys exhibiting CsA nephropathy. CsA administration increased p-FoxO1 expression and decreased p-FoxO3a expression, whereas concurrent statin treatment reversed these changes, increased the expression of the antioxidant enzymes MnSOD and hemeoxygenase-1 and decreased the expression of the pro-apoptotic protein Bim. CONCLUSION: Statin-mediated upregulation of klotho expression and differential regulation of FoxO expression promote resistance to CsA-induced oxidative stress.


Assuntos
Envelhecimento/metabolismo , Glucuronidase/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Pravastatina/farmacologia , Regulação para Cima/fisiologia , Envelhecimento/efeitos dos fármacos , Animais , Ciclosporina , Imunossupressores , Rim/efeitos dos fármacos , Nefropatias/induzido quimicamente , Masculino , Camundongos , Regulação para Cima/efeitos dos fármacos
15.
PLoS One ; 7(7): e42011, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22848688

RESUMO

Accumulating evidence suggests that Th17 cells play a role in the development of chronic allograft injury in transplantation of various organs. However, the influence of current immunosuppressants on Th17-associated immune responses has not been fully investigated. We prospectively investigated the changes in Th17 cells in peripheral blood mononuclear cells (PBMCs) collected before and 1 and 3 months after KT in 26 patients and we investigated the suppressive effect of tacrolimus on Th17 in vitro. In the early posttransplant period, the percentage of Th17 cells and the proportion of IL-17-producing cells in the effector memory T cells (TEM) were significantly increased at 3 months after transplantation compared with before transplantation (P<0.05), whereas Th1/Th2 cells and TEM cells were significantly decreased. The degree of increase in Th17 during the early posttransplant period was significantly associated with allograft function at 1 year after transplantation (r = 0.4, P<0.05). In vitro, tacrolimus suppressed Th1 and Th2 cells in a concentration-dependent manner, but did not suppress Th17 cells even at high concentration. This suggests that current immunosuppression based on tacrolimus is inadequate to suppress Th17 cells in KTRs, and dysregulation of Th17 may be associated with the progression of CAD.


Assuntos
Inibidores de Calcineurina , Inibidores Enzimáticos/farmacologia , Imunossupressão/métodos , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Transplante Homólogo/efeitos adversos , Adulto , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Feminino , Seguimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Tacrolimo/farmacologia , Células Th17/metabolismo , Fatores de Tempo
16.
Transplantation ; 94(3): 218-25, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22790389

RESUMO

BACKGROUND: The study was performed to investigate the influence of cyclosporine A (CsA)-induced renal injury on autophagy in an experimental model of chronic CsA nephropathy. METHODS: Three dosages of CsA (7.5, 15, and 30 mg/kg/day) were administered to mice for 4 weeks. The formation of autophagosomes was measured with microtubule-associated protein 1 light chain 3 phospholipid-conjugated form (LC3-II) and beclin-1, and the ability of autophagic clearance was examined with sequestosome-1 (p62). Autophagic vacuoles were visualized and counted using electron microscopy. Double immunolabeling of LC3-II and active caspase-3 was performed to evaluate the association between autophagy and apoptosis. Oxidative stress was evaluated by measuring urinary 8-hydroxy-2'-deoxyguanosine excretion, demonstrating oxidative DNA damage. Antioxidative drugs, pravastatin and N-acetylcysteine, were used to evaluate the role of CsA-induced oxidative stress on autophagy. RESULTS: CsA treatment increased the expressions of LC3-II and beclin-1 in the kidney in a dose-dependent manner. The number of p62-positive cells was also significantly increased in a CsA dose-dependent manner. Electron microscopy revealed excessive autophagic vacuoles in the CsA group compared with the vehicle group. Expression of active caspase-3 was increased in a CsA dose-dependent manner and was colocalized with LC3-II in the injured area of CsA-treated kidneys. Concurrent pravastatin or N-acetylcysteine treatment reduced urinary excretion of 8-hydroxy-2'-deoxyguanosine and subsequently decreased LC3-II expression and the number of p62-positive cells compared with the CsA group. CONCLUSIONS: Chronic CsA nephropathy is a state of excessive autophagic vacuoles and decreased autophagic clearance. Oxidative stress may play an importation role in the induction of autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Ciclosporina/toxicidade , Nefropatias/patologia , 8-Hidroxi-2'-Desoxiguanosina , Acetilcisteína/uso terapêutico , Animais , Antioxidantes/metabolismo , Apoptose , Caspase 3/biossíntese , Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/biossíntese , Nefropatias/etiologia , Masculino , Camundongos , Microscopia Eletrônica/métodos , Proteínas Associadas aos Microtúbulos/biossíntese , Estresse Oxidativo , Fagossomos/metabolismo , Pravastatina/uso terapêutico , Fatores de Tempo
17.
Ren Fail ; 34(8): 974-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22817654

RESUMO

The adequate rituximab (RTX) dosage in ABO-incompatible transplantation (ABO-IKT) remains undetermined. We used two kinds of RTX dosage groups [low RTX (100 mg/m(2)) and typical RTX (375 mg/m(2)) dosage groups] according to immunologic risks and investigated the change of B-cell, anti-ABO antibodies, and the clinical outcome in ABO-IKT according to the RTX dose. Fifteen patients with high immunologic risk [panel reactive antibody (PRA) > 50%, retransplant, AB to O transplant] were assigned to typical RTX group and 17 patients without risk were assigned to low RTX group. We compared the changes of B-cell, anti-ABO antibody titer, required number of plasmapheresis (PP), and the clinical outcome after transplantation between the two groups. After infusion of RTX, peripheral blood B-cell counts were successfully depleted to <1% in both groups. Before kidney transplantation (KT), the minimal number of PP to achieve the target titer (1:16) (2.6 ± 2.7 vs. 2.2 ± 2.5; p = 0.66) and the titer reduction rate of anti-ABO antibodies did not differ between the two groups (low RTX: 1.52 ± 1.21 vs. typical RTX: 1.53 ± 1.20, p = 0.94). After KT, anti-ABO antibody titer was suppressed less than 1:32 in both groups up to posttransplant 1 year. The allograft function and infectious complication did not differ between the two groups as well. In ABO-IKT, low RTX is comparable with typical RTX dosing with respect to B-cell depletion, antibody rebound suppression, the effect on clinical outcome in patients with low immunologic risk.


Assuntos
Sistema ABO de Grupos Sanguíneos/imunologia , Anticorpos Monoclonais Murinos/administração & dosagem , Linfócitos B/imunologia , Incompatibilidade de Grupos Sanguíneos/imunologia , Dessensibilização Imunológica/métodos , Fatores Imunológicos/administração & dosagem , Transplante de Rim/imunologia , Adulto , Incompatibilidade de Grupos Sanguíneos/tratamento farmacológico , Feminino , Humanos , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Plasmaferese , Risco , Rituximab , Imunologia de Transplantes
18.
J Korean Med Sci ; 27(2): 160-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22323863

RESUMO

Sirolimus (SRL) is a promising drug for replacing calcineurin inhibitors. We performed this study to determine the optimal time of conversion from cyclosporine (CsA) to SRL in an experimental model of chronic CsA nephropathy. Three separate studies were performed. In the first study, SRL was given to rats with or without CsA for 4 weeks. In the second study, rats were treated initially with CsA for 1 week, and then switched to SRL (early conversion). In the third study, CsA was given for 4 weeks and then replaced by SRL for 4 weeks treatment of CsA (late conversion). The influence of SRL on CsA-induced renal injury was evaluated by assessing renal function, histopathology (interstitial inflammation and fibrosis), and apoptotic cell death. Combined CsA and SRL treatment significantly impaired renal function, increased apoptosis, and interstitial fibrosis and inflammation compared with CsA or SRL treatment alone. Early conversion to SRL did not change renal function, histopathology, or apoptosis compared with early CsA withdrawal. By contrast, late conversion to SRL significantly aggravated these parameters compared with late CsA withdrawal. In conclusion, early conversion from CsA to SRL is effective in preventing CsA-induced renal injury in a setting of CsA-induced renal injury.


Assuntos
Ciclosporina/toxicidade , Imunossupressores/farmacologia , Nefropatias/patologia , Sirolimo/farmacologia , Animais , Apoptose/efeitos dos fármacos , Doença Crônica , Intestinos/efeitos dos fármacos , Intestinos/patologia , Nefropatias/induzido quimicamente , Masculino , Modelos Animais , Ratos , Ratos Sprague-Dawley
19.
Transplantation ; 93(4): 383-9, 2012 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-22267156

RESUMO

BACKGROUND: It is known that sirolimus (SRL) aggravates cyclosporine A (CsA)-induced nephrotoxicity and pancreatic injury, but the influence of everolimus (EVR) on CsA-induced organ injury is undetermined. METHODS: Rats were treated with CsA (15 mg/kg) and EVR or SRL (0.3 mg/kg) subcutaneously for 4 weeks. The influences of EVR or SRL on CsA-induced nephrotoxicity and pancreatic islet dysfunction were compared, and drug interactions between CsA and EVR or SRL were evaluated at blood and tissue levels. RESULTS: Treatment with EVR or SRL alone did not cause severe pancreatic dysfunction and renal injury, but when combined with CsA they aggravated CsA-induced pancreatic and renal injury. Drug interactions between CsA and EVR or SRL differed at the tissue level. Combined treatment with CsA and SRL significantly increased the CsA or SRL levels in kidney and pancreas compared with CsA or SRL alone. However, combined treatment with CsA and EVR did not increase CsA or EVR levels in kidney and pancreas. CONCLUSIONS: Both EVR and SRL aggravate CsA-induced organ injury, but the pharmacologic interaction between EVR and CsA at the tissue level is less than that between CsA and SRL. This finding provides better understanding of the difference between EVR and SRL when combined with CsA treatment.


Assuntos
Ciclosporina/farmacologia , Inibidores Enzimáticos/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Rim/efeitos dos fármacos , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Everolimo , Imunossupressores/farmacologia , Ilhotas Pancreáticas/fisiopatologia , Rim/patologia , Masculino , Modelos Animais , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
20.
Exp Mol Med ; 43(11): 630-7, 2011 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-21865860

RESUMO

The aim of this study was to evaluate whether the Th17 and Treg cell infiltration into allograft tissue is associated with the severity of allograft dysfunction and tissue injury in acute T cell-mediated rejection (ATCMR). Seventy-one allograft tissues with biopsy-proven ATCMR were included. The biopsy specimens were immunostained for FOXP3 and IL-17. The allograft function was assessed at biopsy by measuring serum creatinine (Scr) concentration, and by applying the modified diet in renal disease (MDRD) formula, which provides the estimated glomerular filtration rate (eGFR). The severity of allograft tissue injury was assessed by calculating tissue injury scores using the Banff classification. The average numbers of infiltrating Treg and Th17 cells were 11.6 ± 12.2 cells/mm² and 5.6 ± 8.0 cells/mm², respectively. The average Treg/Th17 ratio was 5.6 ± 8.2. The Treg/Th17 ratio was significantly associated with allograft function (Scr and MDRD eGFR) and with the severity of interstitial injury and tubular injury (P < 0.05, all parameters). In separate analyses of the number of infiltrating Treg and Th17 cells, Th17 cell infiltration was significantly associated with allograft function and the severity of tissue injury. By contrast, Treg cell infiltration was not significantly associated with allograft dysfunction or the severity of tissue injury. The results of this study show that higher infiltration of Th17 cell compared with Treg cell is significantly associated with the severity of allograft dysfunction and tissue injury.


Assuntos
Rejeição de Enxerto/etiologia , Interleucina-17/metabolismo , Transplante de Rim/efeitos adversos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Doença Aguda , Creatinina/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Rejeição de Enxerto/patologia , Humanos , Técnicas Imunoenzimáticas , Estudos Retrospectivos , Linfócitos T Reguladores/patologia , Células Th17/patologia , Transplante Homólogo
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