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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.
Korean J Intern Med ; 30(6): 759-70, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26552451

RESUMO

Despite strict pre- and post-transplantation screening, the incidence of new-onset diabetes after transplantation (NODAT) remains as high as 60%. This complication affects the risk of cardiovascular events and patient and graft survival rates. Thus, reducing the impact of NODAT could improve overall transplant success. The pathogenesis of NODAT is multifactorial, and both modifiable and nonmodifiable risk factors have been implicated. Monitoring and controlling the blood glucose profile, implementing multidisciplinary care, performing lifestyle modifications, using a modified immunosuppressive regimen, administering anti-metabolite agents, and taking a conventional antidiabetic approach may diminish the incidence of NODAT. In addition to these preventive strategies, inhibition of dipeptidyl peptidase-4 (DPP4) by the gliptin family of drugs has recently gained considerable interest as therapy for type 2 diabetes mellitus and NODAT. This review focuses on the role of DPP4 inhibitors and discusses recent literature regarding management of NODAT.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Transplante de Órgãos/efeitos adversos , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/enzimologia , Diabetes Mellitus/etiologia , Humanos , Medição de Risco , Fatores de Risco , Resultado do Tratamento
7.
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
8.
Nephrol Dial Transplant ; 23(11): 3437-45, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18558621

RESUMO

BACKGROUND AND METHODS: Tissue transglutaminase (tTG) may induce pro-inflammatory cytokines and produce irreversible end-products, thus promoting renal scarring. It has recently been confirmed that the crescent formation in murine experimental crescentic glomerulonephritis (ecGN) has been inhibited by the administration of recombinant uteroglobin (rUG). However, the ability of UG on tTG modulation has not been thoroughly assessed. In this study, we investigated the feasible protective role of UG in murine ecGN through the modulation of tTG and TGF-beta1 expressions. ecGN was induced by the administration of anti-GBM Ab into C57BL/6 mice. RESULTS: Both proteinuria and BUN levels were distinctively lower in rUG-treated mice compared to those of disease control mice. Glomerular injuries such as mesangial proliferation, matrix production and crescent formation were lessened with the rUG treatment, and these findings were parallel with the attenuated expression of tTG and TGF-beta1. tTG and TGF-beta1 were expressed mainly on mesangial areas by the induction of ecGN and rUG treatment markedly attenuated the expressions of these proteins in glomeruli without spatial changes. With the addition of LPS to mesangial cells, the expressions of tTG and TGF-beta1 were up-regulated, whilst the addition of cysteamine, tTG inhibitor, attenuated the expression of tTG and TGF-beta1 as well as the cellular proliferation which was further induced by LPS. CONCLUSION: We demonstrate for the first time that rUG is able to attenuate the renal injury through the modulation of expressions of tTG and TGF-beta1 in ecGN and further suggest a wide range of feasible molecular targets to reduce the severity of human glomerulonephritis.


Assuntos
Glomerulonefrite/metabolismo , Células Mesangiais/metabolismo , Transglutaminases/metabolismo , Uteroglobina/farmacologia , Animais , Anticorpos Anti-Idiotípicos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/patologia , Humanos , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/farmacologia , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta1/metabolismo
9.
Clin Immunol ; 124(3): 258-66, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17662658

RESUMO

Although NKT cells expressing CD1d-reactive TCR exerted protective role in autoimmune diseases, the regulatory function of CD1d-dependent NKT cells in alloimmune responses has not been investigated thoroughly. Here, we demonstrated the regulatory effects of NKT cells using a pancreas islet transplantation model. CD40/CD154 blocking induced long-term graft survival in most B6 recipients, but B6.CD1d(-/-) recipients showed co-stimulation blockade-resistant rejection. Adoptive transfer of NKT cells into B6.CD1d(-/-) restored tolerizing capacity of co-stimulatory blockade. Activation of NKT cells was effective for the prolongation of graft survival and up-regulated membrane-bound TGF-beta expression transiently on their cell surface. The activated CD1d-dependent NKT cells inhibited alloantigen-driven cell proliferation through cell contacts and the beneficial effect of CD154 blocking for allograft survival was related to TGF-beta pathway. Thus, we can conclude that NKT cells are essential for the stable allograft survival and the regulatory function is dependent on, at least in part, TGF-beta engagement.


Assuntos
Antígenos CD1/metabolismo , Sobrevivência de Enxerto/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Células Matadoras Naturais/imunologia , Animais , Antígenos CD1/genética , Antígenos CD1d , Antígenos de Histocompatibilidade Classe II/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismo , Tolerância ao Transplante/imunologia , Regulação para Cima
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