RESUMO
RATIONALE & OBJECTIVE: Reduced kidney function is associated with an increased risk of cancer; however, it is unclear if cancer increases the risk of kidney failure with replacement therapy (KFRT). We assessed the risk of KFRT among patients with various types of cancer collectively and with specific types of cancer. STUDY DESIGN: Retrospective population-based cohort study. SETTING & PARTICIPANTS: A total of 2,473,095 participants with (n = 824,365) or without (n = 1,648,730) cancer registered in the Korean National Health Insurance Service database. PREDICTORS: Cancer and cancer subtypes defined using International Classification of Diseases, 10th Revision, Clinical Modification, codes. OUTCOMES: Primary outcome was KFRT defined as the initiation of hemodialysis or peritoneal dialysis or kidney transplantation. ANALYTICAL APPROACH: For each patient with cancer, 2 controls matched for age, sex, estimated glomerular filtration rate, diabetes, and hypertension were included. To address the competing risk of death, a competing risk survival analysis was conducted using the Fine and Gray method. RESULTS: Occurrence of KFRT was higher in patients with cancer than in controls without cancer (incidence rates of 1.07 vs 0.51 cases per 1,000 person-years). Competing risk analysis showed that cancer was significantly associated with an increased risk of KFRT after adjusting for other potential predictors (adjusted hazard ratio, 2.29 [95% CI, 2.20-2.39]). Multiple myeloma, leukemia, lymphoma, and kidney, ovarian, and liver cancer were most significantly associated with an increased KFRT risk, with multiple myeloma conferring the highest risk across age and sex groups. All subgroups of patients with cancer (based on age, sex, smoking, alcohol, exercise, obesity, and comorbid conditions) exhibited a higher risk of KFRT. LIMITATIONS: Causal association between cancer and kidney outcomes could not be confirmed. CONCLUSIONS: Patients with cancer, particularly those with multiple myeloma, exhibited an increased risk of KFRT after accounting for the competing risk of death.
Assuntos
Falência Renal Crônica , Neoplasias , Insuficiência Renal , Estudos de Coortes , Humanos , Falência Renal Crônica/terapia , Neoplasias/epidemiologia , Diálise Renal , Insuficiência Renal/epidemiologia , Insuficiência Renal/terapia , República da Coreia/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: The reactive oxygen species (ROS) and inflammation, a critical contributor to tissue damage, is well-known to be associated with various disease. The kidney is susceptible to hypoxia and vulnerable to ROS. Thus, the vicious cycle between oxidative stress and renal hypoxia critically contributes to the progression of chronic kidney disease and finally, end-stage renal disease. Thus, delivering therapeutic agents to the ROS-rich inflammation site and releasing the therapeutic agents is a feasible solution. RESULTS: We developed a longer-circulating, inflammation-sensing, ROS-scavenging versatile nanoplatform by stably loading catalase-mimicking 1-dodecanethiol stabilized Mn3O4 (dMn3O4) nanoparticles inside ROS-sensitive nanomicelles (PTC), resulting in an ROS-sensitive nanozyme (PTC-M). Hydrophobic dMn3O4 nanoparticles were loaded inside PTC micelles to prevent premature release during circulation and act as a therapeutic agent by ROS-responsive release of loaded dMn3O4 once it reached the inflammation site. CONCLUSIONS: The findings of our study demonstrated the successful attenuation of inflammation and apoptosis in the IRI mice kidneys, suggesting that PTC-M nanozyme could possess promising potential in AKI therapy. This study paves the way for high-performance ROS depletion in treating various inflammation-related diseases.
Assuntos
Injúria Renal Aguda , Injúria Renal Aguda/tratamento farmacológico , Animais , Catalase , Feminino , Humanos , Hipóxia , Inflamação/tratamento farmacológico , Masculino , Camundongos , Estresse Oxidativo , Espécies Reativas de OxigênioRESUMO
We present electrophysiological (EP) signals correlated with cellular cell activities in the adrenal cortex and medulla using an adrenal gland implantable flexible EP probe. With such a probe, we could observe the EP signals from the adrenal cortex and medulla in response to various stress stimuli, such as enhanced hormone activity with adrenocorticotropic hormone, a biomarker for chronic stress response, and an actual stress environment, like a forced swimming test. This technique could be useful to continuously monitor the elevation of cortisol level, a useful indicator of chronic stress that potentially causes various diseases.
Assuntos
Glândulas Suprarrenais/fisiopatologia , Fenômenos Eletrofisiológicos/fisiologia , Estresse Fisiológico/fisiologia , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/fisiopatologia , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Animais , Masculino , Bulbo/metabolismo , Bulbo/fisiopatologia , RatosRESUMO
BACKGROUND: Recently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Faslpr mutation were also treated with HGC vehicle and used as healthy controls. RESULTS: Weekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-ß1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone. CONCLUSION: Our study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice.
Assuntos
Quitosana/farmacologia , Quitosana/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Micelas , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Animais , Apoptose , Quitosana/química , Feminino , Fibrose/patologia , Expressão Gênica , Interações Hidrofóbicas e Hidrofílicas , Inflamação , Rim/lesões , Rim/patologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , NF-kappa B/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Although anastomosing hemangiomas are very rare and benign vascular neoplasms, these tumors are more common among patients with end-stage kidney disease. Incidental finding of these tumors in the kidney or adrenal gland has been reported. Herein, we describe a case in which an anastomosing hemangioma was misdiagnosed as a renal cell carcinoma before kidney transplant. CASE PRESENTATION: A 35-year-old woman with lupus nephritis was admitted to our emergency department for suspected uremic symptoms of nausea and general weakness. She had received hemodialysis due to end-stage kidney disease, and a living-donor kidney transplantation from her father was planned. On pre-operative contrast-enhanced computed tomography and magnetic resonance imaging, a 1.7 cm renal cell carcinoma was observed in the right kidney. On staining after radical nephrectomy, irregularly shaped vascular spaces of various sizes were observed, with these spaces having an anastomosing pattern. As the findings of the anastomosing hemangioma are similar to those of a renal cell carcinoma on imaging, histology examination was necessary to confirm the diagnosis of anastomosing hemangioma and to prevent delay in listing for kidney transplantation. Good kidney function was achieved after transplantation, with no tumor recurrence. CONCLUSION: Our case underlines the importance for prompt surgical resection of an enhancing renal mass to confirm diagnosis in patients scheduled for kidney transplantation to avoid any delay.
Assuntos
Carcinoma de Células Renais/diagnóstico , Hemangioma , Falência Renal Crônica , Transplante de Rim/métodos , Rim , Nefrectomia/métodos , Adulto , Diagnóstico Diferencial , Erros de Diagnóstico/prevenção & controle , Feminino , Hemangioma/diagnóstico , Hemangioma/fisiopatologia , Hemangioma/cirurgia , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Rim/cirurgia , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/cirurgia , Nefrite Lúpica/complicações , Nefrite Lúpica/diagnóstico , Imageamento por Ressonância Magnética/métodos , Diálise Renal/métodos , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
Renal fibrosis is the common pathway of chronic kidney disease progression. The nuclear receptor farnesoid X receptor [FXR, NR1H4 (nuclear receptor subfamily 1 group member 4)], a multifunctional transcription factor, plays a pivotal role in protecting against fibrosis. However, the mechanisms underlying these antifibrotic actions of FXR in kidney disease are largely unknown. Here, we show that agonist GW4064-mediated FXR activation inhibits the activity of the nonreceptor tyrosine kinase Src (proto-oncogene tyrosine-protein kinase), which is critical for regulation of yes-associated protein (YAP) phosphorylation and nuclear localization in renal fibrosis. Activation of FXR suppressed renal fibrosis and Tyr416-Src phosphorylation in TGF-ß-treated human renal proximal tubule epithelial (HK2) cells. Moreover, GW4064 treatment in HK2 cells increased Ser127 phosphorylation, cytosolic accumulation of YAP, and interaction of the hippo core kinases (Ste20-like kinase 1, large tumor suppressor kinase 1, and salvador homolog 1). Inhibition of Src using PP2 (Src kinase inhibitor) prevented renal fibrosis and increased Ser127 phosphorylation and cytosolic accumulation of YAP. The expression of fibrosis markers, inflammatory genes, and YAP target genes was increased in the kidneys of FXR knockout mice compared with those of wild-type mice. In addition, GW4064 or WAY-362450 (turofexorate isopropyl) treatment protected against unilateral ureteral obstruction-induced renal fibrosis. Collectively, our data support the novel conclusion that Src-mediated crosstalk between FXR and YAP protects against renal fibrosis, making this pathway a possible therapeutic target for chronic kidney disease.-Kim, D.-H., Choi, H.-I., Park, J. S., Kim, C. S., Bae, E. H., Ma, S. K., Kim, S. W. Src-mediated crosstalk between FXR and YAP protects against renal fibrosis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fibrose/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Quinases da Família src/metabolismo , Animais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Isoxazóis/farmacologia , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Proto-Oncogene Mas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteínas de Sinalização YAPRESUMO
BACKGROUND INFORMATION: Tubulointerstitial fibrosis is the end-point of chronic kidney diseases. Tamoxifen, a selective oestrogen receptor (ER) modulator, attenuates renal fibrosis, by regulating the transforming growth factor (TGF)-ß/Smad signalling. Src and phosphoinositide 3-kinase (PI3K)/Akt pathways play critical roles in the pathogenesis of renal fibrosis. However, the activation of the non-canonical TGF-ß signalling in renal fibrosis after treatment with tamoxifen remains unclear. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) in rats. Tamoxifen was orally administered after UUO. Additionally, HK-2 cells were treated with tamoxifen in the presence or absence of TGF-ß1. The selective ER down-regulator ICI and ER-α silencing were used to confirm the involvement of ER-α on the effect of tamoxifen on TGF-ß1-stimulated fibrosis in HK-2 cells. RESULTS: Tamoxifen treatment ameliorated UUO-induced renal fibrosis as shown by decreased expression of α-smooth muscle actin (SMA), fibronectin and connective tissue growth factor (CTGF). The phosphorylation of Src, PI3K, Akt, mammalian target of rapamycin (mTOR) and p70S6K significantly decreased in UUO kidneys from tamoxifen-treated animals. Tamoxifen dose-dependently suppressed the TGF-ß1-induced expression of α-SMA and CTGF, and phosphorylation of Src, PI3K, Akt, mTOR and p70S6K in HK-2 cells. These anti-fibrotic effects were reversed by treatment with ICI and silencing of ER-α. Moreover, inhibition of the PI3K/Akt and mTOR/p70S6K pathways was observed in HK-2 cells co-treated with PP1 (a Src kinase inhibitor) and tamoxifen. CONCLUSIONS: The anti-fibrotic effects of tamoxifen are associated with the suppression of Src kinase function via ER-α, followed by inhibition of the PI3K/Akt and mTOR/p70S6K signalling pathways. SIGNIFICANCE: Our findings suggest that tamoxifen is a novel therapeutic option for the prevention and treatment of renal fibrosis.
Assuntos
Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/farmacologia , Animais , Masculino , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/metabolismo , Quinases da Família src/metabolismoRESUMO
Histone deacetylases have been a target of therapy for organ fibrosis. Here, we report the protective effect of CG200745 (CG), a novel histone deacetylase inhibitor, on tubulointerstitial fibrosis in Col4a3-/- mice, a murine model of Alport syndrome. Morphological analyses revealed CG treatment markedly alleviated kidney fibrosis in Col4a3-/- mice at the age of 7 weeks. CG prevented the activation of transforming growth factor ß (TGFß) and its downstream SMAD signaling in the kidney of Col4a3-/- mice. As critical upstream regulators of TGFß signaling, immunoblotting of whole kidney lysate of Col4a3-/- mice reveled that intra-renal renin-angiotensin system (RAS) was activated with concurrent upregulation of inflammation and apoptosis, which were effectively suppressed by CG treatment. CG suppressed both activation of RAS and up-regulation of TGFß signals in angiotensin II-stimulated HK-2 cells, a human kidney proximal tubular epithelial cell line. CG inhibited activation of TGFß-driven signals and fibrosis in NRK-49F cells, a rat kidney fibroblast cell line, under angiotensin II-rich conditions. Collectively, CG was found to be effective both in proximal tubular epithelial cells by inhibiting local RAS and TGFß signaling activation, as well as in fibroblasts by blocking their transition to myofibroblasts, attenuating renal fibrosis in a murine model of Alport syndrome.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Túbulos Renais Proximais/metabolismo , Naftalenos/farmacologia , Nefrite Hereditária , Transdução de Sinais , Animais , Autoantígenos/metabolismo , Linhagem Celular , Colágeno Tipo IV/deficiência , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Fibrose , Humanos , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Knockout , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/genética , Nefrite Hereditária/metabolismo , Nefrite Hereditária/patologia , Ratos , Fator de Crescimento Transformador beta/metabolismoRESUMO
OBJECTIVES: Cardiac involvement is present in more than half of the patients with systemic lupus erythematosus (SLE). However, large-scale studies on the prevalence of atrial fibrillation (AF) in this disease do not exist. We aimed to investigate the incidence and clinical significance of AF in SLE. METHODS: Patients with SLE (n=21,143; mean age, 41.8±13.13 years; female, 90.38%) without previous AF were selected from the Korean National Health Insurance Service National Sample Cohort database between 2008 and 2014. Age-and sex-matched controls (n=105,715) were randomly sampled in a 5:1 ratio from the population of individuals without SLE from the same database. Both cohorts were followed-up for incidental AF and death until 2015. RESULTS: AF was newly detected in 481 (2.27%) patients with SLE and 619 (0.59%) controls (incidence: 3.692 and 0.941 per 1000 person-years, respectively). After multivariate adjustment, SLE was found to be a risk factor for developing AF [hazard ratio (HR), 2.84; 95% confidence interval (CI), 2.50-3.23]. On subgroup analysis, younger (age <40) patients showed a higher incidence of AF. SLE patients with incidental AF had a higher mortality rate compared with patients without SLE with AF (HR, 2.35; 95% CI 1.73-3.20) and those with SLE without AF (HR, 3.53; 95% CI 2.84-4.39) after adjustment. CONCLUSIONS: SLE was an independent risk factor for AF development, especially in younger patients without previous AF, stressing the importance of cardiac assessment in this population. Development of AF in patients with SLE was associated with increased mortality.
Assuntos
Fibrilação Atrial , Lúpus Eritematoso Sistêmico , Adulto , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , TaiwanRESUMO
BACKGROUND/AIMS: Both arterial stiffness and coronary artery calcification (CAC) are important predictors of cardiovascular disease in the general population and in chronic kidney disease (CKD) patients. Recent studies on arterial stiffness and CAC in subjects with preserved renal function have verified the association between the two. However, the relationship is not well evaluated in CKD patients. METHODS: This cross-sectional study analyzed 1,385 predialysis CKD patients from the KNOW-CKD cohort. Participants were divided into four groups according to brachial-ankle pulse wave velocity (baPWV) quartile. Coronary artery calcium scores (CACS) were assessed using cardiac computed tomography and CAC was defined as a CACS >100. RESULTS: CAC prevalence was higher in the higher baPWV groups (6.4, 9.8, 23.7, and 43.8% for the 1st to 4th quartiles of baPWV, respectively, p < 0.001). In Tobit regression analyses that were fully adjusted for traditional and renal cardiovascular risk factors, the CACS ratio comparing the highest and lowest baPWV quartiles was 3.03 (95% CI, 1.59-6.87). Similarly, the OR for CAC in the highest baPWV quartile compared to the lowest quartile was 1.98 (95% CI, 1.09-3.60) in a fully adjusted multivariate logistic model. Results were consistent across analyses with different cutoffs for CAC or with different clinically relevant subgroups. CONCLUSION: Increased arterial stiffness measured by high baPWV was associated with CAC in a predialysis CKD cohort. Longitudinal studies are needed to determine the effect of arterial stiffness on the development or progression of CAC in CKD.
Assuntos
Doença da Artéria Coronariana/metabolismo , Insuficiência Renal Crônica/complicações , Calcificação Vascular , Rigidez Vascular , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Análise de Onda de Pulso , Fatores de RiscoRESUMO
BACKGROUND: Obstructive sleep apnea (OSA) is known to be associated with metabolic dysregulation and incident cardiovascular diseases. However, its association with end-stage renal disease (ESRD) has not been clarified. This study aimed to evaluate longitudinally whether OSA is an independent risk factor for ESRD. METHODS: This retrospective nationwide population-based cohort study included data on 67,359 patients with OSA and 336,795 age-, sex- and years of the enrollment-matched controls without OSA obtained from the Korean National Health Insurance Service database from 2009 to 2014. The study population was followed up from baseline to the date of ESRD diagnosis or until 2016. A Cox proportional-hazards model with multivariable adjustment was used to evaluate the association between OSA and incident ESRD. RESULTS: A significantly higher incident ESRD risk (adjusted hazard ratio: 1.29, 95% confidence interval 1.02-1.62) was observed for patients older than 40 years with OSA than for matched controls, when adjusted for age, sex, income status, smoking, alcohol consumption, body mass index, diabetes, hypertension, dyslipidemia, estimated glomerular filtration rate, and proteinuria. The OSA group remained predictive of higher risk of ESRD incidence in subgroups of age ≥ 65 years, female sex, hypertension, dyslipidemia, proteinuria, and chronic kidney disease. CONCLUSION: OSA was associated with a higher risk of incident ESRD. Understanding the association between OSA and ESRD might provide further insights to establish national health care policy.
Assuntos
Falência Renal Crônica/epidemiologia , Apneia Obstrutiva do Sono/epidemiologia , Adulto , Idoso , Comorbidade , Feminino , Humanos , Incidência , Falência Renal Crônica/diagnóstico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , República da Coreia/epidemiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Apneia Obstrutiva do Sono/diagnóstico , Fatores de TempoRESUMO
BACKGROUND: Nephrogenic diabetes insipidus (DI) secondary to a urinary tract obstruction is a rare condition. Herein, we report a case of partial nephrogenic DI due to obstructive uropathy in a patient with Castleman's disease. CASE PRESENTATION: A 78-year-old man underwent computed tomography (CT) at his local hospital because of persistent edema of the leg and polyuria (both lasting approximately 2 months); retroperitoneal fibrosis was detected on the CT scan. An abdominal CT scan showed bilateral hydronephrosis, and a surgical biopsy of the para-aortic lymph node revealed Castleman's disease. To resolve the hydronephrosis, a double J stent was inserted; however, his polyuria continued. As his serum osmolality (311 mOsm/kg) was greater than 300 mOsm/kg, and his serum sodium level was 149 mEq/L, a water deprivation test was not performed. On a vasopressin challenge test, his urine was not sufficiently concentrated to the expected range, indicating partial nephrogenic DI. He was treated with hydrochlorothiazide (25 mg/day), and his urine output gradually decreased to within the normal range. The patient recovered uneventfully and underwent treatment for Castleman's disease. CONCLUSION: To the best of our knowledge, this is the first case of partial nephrogenic DI due to obstructive uropathy associated with Castleman's disease.
Assuntos
Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/diagnóstico por imagem , Diabetes Insípido Nefrogênico/complicações , Diabetes Insípido Nefrogênico/diagnóstico por imagem , Idoso , Hiperplasia do Linfonodo Gigante/urina , Diabetes Insípido Nefrogênico/urina , Humanos , MasculinoRESUMO
G-protein-coupled receptor 40 (GPR40) has an anti-apoptotic effect in pancreatic ß-cells. However, its role in renal tubular cell apoptosis remains unclear. To explore the role of GPR40 in renal tubular apoptosis, a two-week unilateral ureteral obstruction (UUO) mouse model was used. The protein expression of GPR40 was decreased, while the Bax/Bcl-2 protein expression ratio, the expression of tumor necrosis factor (TNF)-α mRNA, and angiotensin II type 1 receptor (AT1R) protein were increased in mice with UUO. In vitro, pretreatment of rat proximal tubular (NRK52E) cells with GW9508, a GPR40 agonist, attenuated the decreased cell viability, increased the Bax/Bcl-2 protein expression ratio, increased protein expression of cleaved caspase-3 and activated the nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit induced by TNF-α treatment. TNF-α treatment significantly increased the expression of AT1R protein and the generation of reactive oxygen species (ROS), whereas GW9508 treatment markedly reversed these effects. Pretreatment with GW1100, a GPR40 antagonist, or silencing of GPR40 in NRK52E cells promoted the increased expression of the cleaved caspase-3 protein by TNF-α treatment. Our results demonstrate that decreased expression of GPR40 is associated with apoptosis via TNF-α and AT1R in the ureteral obstructed kidney. The activation of GPR40 attenuates TNF-α-induced apoptosis by inhibiting AT1R expression and ROS generation through regulation of the NF-κB signaling pathway.
Assuntos
Injúria Renal Aguda/metabolismo , Apoptose/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Apoptose/genética , Biomarcadores , Modelos Animais de Doenças , Imunofluorescência , Expressão Gênica , Imuno-Histoquímica , Túbulos Renais Proximais/patologia , Masculino , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Obstrução Ureteral/complicações , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismoRESUMO
Receptor tyrosine kinases (RTKs) play important roles in the pathogenic processes of kidney fibrosis. However, the pathophysiological roles of recepteur d'origine nantais (RON), one of the receptor tyrosine kinases, have not yet been defined. We investigated whether the activation or sequence-specific small interfering RNA (siRNA) suppression of RON could regulate epithelial mesenchymal transition (EMT) and the expression of pro-fibrotic markers, and its underlying molecular mechanisms. Stable cell lines and transient transfection for RON and the transfected cells of siRNA for RON were developed to investigate the molecular mechanisms in human kidney proximal tubular epithelial (HK-2) and interstitial fibroblasts (NRK49F) cells. RON overexpression induced EMT and increased expression of fibrosis-related proteins such as N-cadherin, vimentin, transforming growth factor-ß (TGFß), αSMA, and fibronectin in HK-2 and NRK49F cells. RON overexpression increased various RTKs and the phosphorylation of Src (Y416) and Smad, while inhibition of RON by siRNA attenuated the expression of EMT- and fibrosis-related proteins and decreased RTKs such as insulin-like growth factor receptor (IGFR), fibroblast growth factor receptor 1 (FGFR1), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), as well as the phosphorylation of Src and Smad pathways. siRNA silencing of Src also attenuated the expression of IGFR, FGFR1, VEGFR, and PDGFR. Inhibition of RON can exert an anti-fibrotic effect by the inhibition of EMT and other RTKs through control of Src and Smad pathways in HK-2 and NRK49F cells.
Assuntos
Transição Epitelial-Mesenquimal , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Quinases da Família src/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Linhagem Celular , Células Epiteliais/metabolismo , Fibroblastos/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Receptores Proteína Tirosina Quinases/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Smad/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Quinases da Família src/genéticaRESUMO
TGF-ß/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-ß/Smad signaling are still needed for their therapeutic targeting. Recently, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was shown to improve renal fibrosis, making it an attractive target for chronic kidney diseases (CKDs). Here, we show the mechanism by which PGC-1α regulates the TGF-ß/Smad signaling pathway using HK-2 cell lines stably overexpressing empty vector (mock cells) or human PGC1α (PGC1α cells). Stable PGC-1α overexpression negatively regulated the expression of TGF-ß-induced epithelial-mesenchymal transition (EMT) markers (fibronectin, E-cadherin, vimentin, and α-SMA) and EMT-related transcription factors (Snail and Slug) compared to mock cells, inhibiting fibrotic progression. Interestingly, among molecules upstream of Smad2/3 activation, the gene expression of only TGFßRI, but not TGFßRII, was downregulated in PGC-1α cells. In addition, the downregulation of TGFßRI by PGC-1α was associated with the upregulation of let-7b/c, miRNA for which the 3' untranslated region (UTR) of TGFßRI contains a binding site. In conclusion, PGC-1α suppresses TGF-ß/Smad signaling activation via targeting TGFßRI downregulation by let-7b/c upregulation.
Assuntos
MicroRNAs/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Insuficiência Renal Crônica/genética , Sítios de Ligação/genética , Linhagem Celular , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica/genética , Humanos , Peroxissomos/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Proteínas Smad/genética , Fatores de Transcrição da Família Snail/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin-angiotensin system (RAS) and transforming growth factor ß (TGFß) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3-/- mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3-/- mice by olmesartan treatment. Upregulation of TGFß and activation of its downstream in Col4a3-/- mice were attenuated by olmesartan in Col4a3-/- mice. Intriguingly, TGFß expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3-/- mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3-/- mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFß-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFß feedback loop to counterbalance intrarenal RAS activation.
Assuntos
Anti-Hipertensivos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Tetrazóis/farmacologia , Fator de Crescimento Transformador beta/genética , Enzima de Conversão de Angiotensina 2 , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Biópsia , Modelos Animais de Doenças , Fibrose , Túbulos Renais/patologia , Camundongos , Camundongos Knockout , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
The novel histone deacetylase inhibitor CG200745 was initially developed to treat various hematological and solid cancers. We investigated the molecular mechanisms associated with the renoprotective effects of CG200745 using deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats. DOCA strips (200 mg/kg) were implanted into rats one week after unilateral nephrectomy. Two weeks after DOCA implantation, DSH rats were randomly divided into two groups that received either physiological saline or CG200745 (5 mg/kg/day) for another two weeks. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson's trichrome staining. The renal expression of fibrosis and inflammatory markers was detected by semiquantitative immunoblotting, a polymerase chain reaction, and immunohistochemistry. Pathological signs such as glomerulosclerosis, tubulointerstitial fibrosis, increased systolic blood pressure, decreased creatinine clearance, and increased albumin-to-creatinine ratios in DSH rats were alleviated by CG200745 treatment compared to those manifestations in positive control animals. Furthermore, this treatment counteracted the increased expression of αSMA, TGF-ß1, and Bax, and the decreased expression of Bcl-2 in the kidneys of DSH rats. It also attenuated the increase in the number of apoptotic cells in DSH rats. Thus, CG200745 can effectively prevent the progression of renal injury in DSH rats by exerting anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.
Assuntos
Acetato de Desoxicorticosterona/efeitos adversos , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Hipertensão/tratamento farmacológico , Nefropatias/prevenção & controle , Naftalenos/administração & dosagem , Actinas/metabolismo , Albuminas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Creatinina/metabolismo , Modelos Animais de Doenças , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/complicações , Nefropatias/metabolismo , Masculino , Naftalenos/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND/AIMS: There is a paucity of literature that investigates a biomarker associated with successful renal recovery following continuous renal replacement therapy (CRRT). Our study aimed to identify potential renal biomarkers or clinical indicators that could predict the successful weaning from CRRT. METHODS: We conducted a prospective, observational study of 110 patients who had received CRRT and were weaned after renal recovery. Patients were considered to have successfully weaned from CRRT once there was no need for renal replacement therapy (RRT) for at least 14 days. For patients who had to restart dialysis within 14 days were considered unsuccessful. RESULTS: Of the 110 patients evaluated, 89 (80.9%) were successfully weaned from CRRT. These patients had lower serum cystatin C (CysC) levels and higher urine output than the group that restarted RRT at the time of CRRT cessation. However, the levels of serum creatinine and neutrophil gelatinase-associated lipocalin were not significantly lower in the successful group compared to the restart-RRT group. A multivariable logistic regression showed that serum CysC was an independent predictor for the successful weaning from CRRT. Furthermore, in a multivariable Cox proportional hazards analysis, the group that was successfully weaned from CRRT had a lower in-hospital mortality compared to the restarted RRT group. CONCLUSION: Serum CysC, at the time of CRRT cessation, is an independent predictor of the successful weaning from CRRT in critically ill patients with acute kidney injury.
Assuntos
Injúria Renal Aguda/terapia , Cistatina C/sangue , Valor Preditivo dos Testes , Terapia de Substituição Renal , Idoso , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Suspensão de TratamentoRESUMO
Tumor necrosis factor-α (TNFα) and the angiotensin system are involved in inflammatory diseases and may contribute to acute kidney injury. We investigated the mechanisms by which TNFα-converting enzyme (TACE) contributes to lipopolysaccharide (LPS)-induced renal inflammation and the effect of TACE inhibitor treatment on LPS-induced cellular injury in human renal proximal tubule epithelial (HK-2) cells. Mice were treated with LPS (10 mg/kg, i.p.) and HK-2 cells were cultured with or without LPS (10 µg/ml) in the presence or absence of a type 1 TACE inhibitor (1 µM) or type 2 TACE inhibitor (10 µM). LPS treatment induced increased serum creatinine, TNFα, and urinary neutrophil gelatinase-associated lipocalin. Angiotensin II type 1 receptor, mitogen activated protein kinase (MAPK), and TACE increased, while angiotensin-converting enzyme-2 (ACE2) expression decreased in LPS-induced acute kidney injury and LPS-treated HK-2 cells. LPS induced reactive oxygen species and the down-regulation of ACE2, and these responses were prevented by TACE inhibitors in HK-2 cells. TACE inhibitors increased cell viability in LPS-treated HK-2 cells and attenuated oxidative stress and inflammatory cytokines. Our findings indicate that LPS activates renin angiotensin system components via the activation of TACE. Furthermore, inhibitors of TACE are potential therapeutic agents for kidney injury.