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1.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206460

RESUMO

Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine's adverse metabolic effects-such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy-was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.


Assuntos
Cromo/deficiência , Clozapina/farmacologia , Intolerância à Glucose/metabolismo , Nefropatias/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Doenças Retinianas/metabolismo , Adipócitos/metabolismo , Animais , Biomarcadores , Pesos e Medidas Corporais , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/genética , Imunofluorescência , Expressão Gênica , Regulação da Expressão Gênica , Imuno-Histoquímica , Insulina/metabolismo , Nefropatias/etiologia , Fígado/metabolismo , Camundongos , Camundongos Obesos , Óxido Nítrico Sintase Tipo II , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Retinianas/etiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
2.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34202940

RESUMO

Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.


Assuntos
Terapia Biológica , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/transplante , Nefropatias/terapia , Células-Tronco Mesenquimais/metabolismo , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/terapia , Animais , Apoptose/efeitos dos fármacos , Terapia Biológica/métodos , Diferenciação Celular , Proliferação de Células/efeitos dos fármacos , Autorrenovação Celular , Fracionamento Químico , Gerenciamento Clínico , Suscetibilidade a Doenças , Exossomos/metabolismo , Humanos , Nefropatias/etiologia , Nefropatias/patologia , Células-Tronco Mesenquimais/citologia , Substâncias Protetoras , Insuficiência Renal/diagnóstico , Insuficiência Renal/etiologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia
3.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204452

RESUMO

Intercellular communication governs multicellular interactions in complex organisms. A variety of mechanisms exist through which cells can communicate, e.g., cell-cell contact, the release of paracrine/autocrine soluble molecules, or the transfer of extracellular vesicles (EVs). EVs are membrane-surrounded structures released by almost all cell types, acting both nearby and distant from their tissue/organ of origin. In the kidney, EVs are potent intercellular messengers released by all urinary system cells and are involved in cell crosstalk, contributing to physiology and pathogenesis. Moreover, urine is a reservoir of EVs coming from the circulation after crossing the glomerular filtration barrier-or originating in the kidney. Thus, urine represents an alternative source for biomarkers in kidney-related diseases, potentially replacing standard diagnostic techniques, including kidney biopsy. This review will present an overview of EV biogenesis and classification and the leading procedures for isolating EVs from body fluids. Furthermore, their role in intra-nephron communication and their use as a diagnostic tool for precision medicine in kidney-related disorders will be discussed.


Assuntos
Biomarcadores/urina , Vesículas Extracelulares/metabolismo , Nefropatias/metabolismo , Animais , Comunicação Celular , Micropartículas Derivadas de Células/metabolismo , Fracionamento Químico , Gerenciamento Clínico , Suscetibilidade a Doenças , Exossomos/metabolismo , Humanos , Nefropatias/diagnóstico , Nefropatias/etiologia , Nefropatias/urina , Biópsia Líquida/métodos , Medicina de Precisão/métodos , Urinálise/métodos
4.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073488

RESUMO

Kidney fibrosis is the final outcome of chronic kidney disease (CKD). Adenosine plays a significant role in protection against cellular damage by activating four subtypes of adenosine receptors (ARs), A1AR, A2AAR, A2BAR, and A3AR. A2AAR agonists protect against inflammation, and A3AR antagonists effectively inhibit the formation of fibrosis. Here, we showed for the first time that LJ-4459, a newly synthesized dual-acting ligand that is an A2AAR agonist and an A3AR antagonist, prevents the progression of tubulointerstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed on 6-week-old male C57BL/6 mice. LJ-4459 (1 and 10 mg/kg) was orally administered for 7 days, started at 1 day before UUO surgery. Pretreatment with LJ-4459 improved kidney morphology and prevented the progression of tubular injury as shown by decreases in urinary kidney injury molecular-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion. Obstruction-induced tubulointerstitial fibrosis was attenuated by LJ-4459, as shown by a decrease in fibrotic protein expression in the kidney. LJ-4459 also inhibited inflammation and oxidative stress in the obstructed kidney, with reduced macrophage infiltration, reduced levels of pro-inflammatory cytokines, as well as reduced levels of reactive oxygen species (ROS). These data demonstrate that LJ-4459 has potential as a therapeutic agent against the progression of tubulointerstitial fibrosis.


Assuntos
Agonistas do Receptor A3 de Adenosina/farmacologia , Nefropatias/tratamento farmacológico , Receptor A2A de Adenosina/metabolismo , Receptor A3 de Adenosina/metabolismo , Obstrução Ureteral/tratamento farmacológico , Agonistas do Receptor A3 de Adenosina/síntese química , Agonistas do Receptor A3 de Adenosina/química , Animais , Fibrose , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Ligantes , Masculino , Camundongos , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
5.
Clin Nephrol ; 96(2): 67-81, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34142945

RESUMO

Coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has now spread into a worldwide pandemic. The pulmonary manifestations of this disease have been well described in literature, however COVID-19 can also cause severe and lasting harm in other organs including the kidneys, heart, and pancreas. Emerging evidence suggests that COVID-19 has multiple renal manifestations which impact the prognosis and mortality of this disease. Here we present a literature review of the current evidence of renal involvement in COVID-19 patients and the potential for future directions in management.


Assuntos
COVID-19/complicações , Nefropatias/etiologia , SARS-CoV-2 , Idoso , COVID-19/mortalidade , COVID-19/terapia , Ensaios Clínicos como Assunto , Feminino , Humanos , Incidência , Nefropatias/epidemiologia , Nefropatias/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
Pan Afr Med J ; 38: 206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995812

RESUMO

Introduction: highly active antiretroviral therapy (HAART) has led to a decline in HIV-induced morbidity and mortality in recent years. However, it has been opined that this has led to elevated risks of cardiovascular diseases (CVDs). This study assessed the risks of CVDs among HAART experienced individuals living with HIV. Methods: a cross sectional study involving 196 adults consisting of 118 HAART experienced and 78 HAART naïve was conducted. Anthropometric and blood pressure measurements were recorded for all participants. Blood samples obtained from the volunteers were used to determine glucose, creatinine, HIV viral load, CD4 count and lipid profile using standard methods. Lipid ratios, atherogenic indices and QRISK3 risk score were calculated. Results: the median CD4 lymphocyte, mean body mass index (BMI) and HDL-c in HAART experienced participants were higher (P<0.05) than HAART naive individuals. The QRISK3 risk score and creatinine were higher (p<0.05) among HAART experienced group. In HAART experienced group, the risk of hypertension, increased low-density lipoprotein (LDL-c), atherogenic index of plasma (AIP) and QRISK3 were 3.7, 2.0, 2.38 and 3.85 times (p<0.05) higher respectively than in HAART naive. Atherogenic coefficient (AC) increase was more prevalent among male (p<0.05) participants. Risk of chronic renal disease (eGFR), hypertension and CVD (as measured by QRISK3) was higher (p<0.05) among the female and older participants respectively. Conclusion: the risk of CVDs and renal disease appeared to be higher among HAART experienced volunteers and older (>45 years) volunteers. The risk of renal disease appeared higher in females.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Doenças Cardiovasculares/etiologia , Infecções por HIV/tratamento farmacológico , Adulto , Fatores Etários , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Feminino , Humanos , Nefropatias/epidemiologia , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Nigéria , Fatores de Risco , Fatores Sexuais
8.
Int Heart J ; 62(3): 546-551, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34053999

RESUMO

Severe aortic stenosis (AS) is often accompanied by renal dysfunction, which portends a poor prognosis. Trans-catheter aortic valve replacement (TAVR) is an accepted therapy for patients with severe AS, whereas the prediction of persistent renal dysfunction following TAVR remains challenging. In this study, we aimed to evaluate the pre-procedural score to assess the reversibility of renal dysfunction following TAVR. A total of 2,588 patients with severe AS who received TAVR and were enrolled in the Optimized transCathEter vAlvular iNtervention (OCEAN-TAVI) multicenter registry (UMIN000020423) were retrospectively investigated and those with serum creatinine (Cre) data at baseline and one year following TAVR were included. The Cre score was calculated using the formula: 0.2 × (age [years]) + 3.6 × (baseline serum Cre [mg/dL]). This score was evaluated to assess the risk of persistent renal dysfunction defined as serum Cre level > 1.5 mg/dL at one year following TAVR. Of the 1705 patients (84.3 ± 5.0 years old) included, 246 (14%) had persistent renal dysfunction following TAVR. The Cre score predicted the incidence of persistent renal dysfunction with an adjusted incidence rate ratio of 1.48 (95% confidence interval 1.42-1.56) with a cutoff of 21.4 (43% versus 5%, P < 0.001). The Cre score also predicted 4-year survival following TAVR (70% versus 52%, P < 0.001) with an adjusted hazard ratio of 1.75 (95% confidence interval 1.29-2.37). In conclusion, the Cre score identified those with a high risk of one-year persistent renal dysfunction following TAVR. The implication of Cre score-guided therapeutic strategy is the next concern.


Assuntos
Estenose da Valva Aórtica/cirurgia , Creatinina/sangue , Nefropatias/fisiopatologia , Substituição da Valva Aórtica Transcateter/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/complicações , Feminino , Humanos , Incidência , Japão/epidemiologia , Nefropatias/sangue , Nefropatias/epidemiologia , Nefropatias/etiologia , Masculino , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Sistema de Registros , Estudos Retrospectivos , Índice de Gravidade de Doença , Substituição da Valva Aórtica Transcateter/mortalidade
9.
Curr Opin Nephrol Hypertens ; 30(4): 444-449, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34027906

RESUMO

PURPOSE OF REVIEW: In this paper, we seek to review coronavirus disease 2019 (COVID-19) associated kidney injury with a focus on what is known about pathophysiology. RECENT FINDINGS: Kidney injury is a common complication of SARS-CoV-2 infection and is associated with increased morbidity and mortality. Acute tubular necrosis and glomerular injury are two common findings. Direct viral effect, endothelial dysfunction, and podocyte and tubular epithelial injury have been described. COVID-19-related glomerular injury may also be associated with high-risk APOL1 genotype. SUMMARY: Data on COVID-19 renal involvement have suggested novel mechanisms of kidney injury that need to be further elucidated. More data are needed on renal involvement in milder disease, renal-specific therapeutic interventions, and long-term sequelae.


Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , COVID-19/complicações , COVID-19/fisiopatologia , Injúria Renal Aguda/genética , Injúria Renal Aguda/terapia , COVID-19/terapia , Genótipo , Humanos , Nefropatias/etiologia , Nefropatias/genética , Nefropatias/fisiopatologia , Nefropatias/terapia
10.
Radiologia ; 63(4): 370-383, 2021.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33931205

RESUMO

In March 2020, the World Health Organization declared a global pandemic of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); epidemic conditions continue in nearly all countries today. Although the symptoms and imaging manifestations of COVID-19 predominantly involve the respiratory system, it is fundamental to know the manifestations of the disease and its possible complications in other organs to help in diagnosis and orient the prognosis. To improve the diagnostic process without increasing the risk of contagion unnecessarily, it is crucial to know when extrathoracic imaging tests are indicated and which tests are best in each situation. This paper aims to provide answers to these questions. To this end, we describe and illustrate the extrathoracic imaging manifestations of COVID-19 in adults as well as the entire spectrum of imaging findings in children.


Assuntos
COVID-19/complicações , COVID-19/diagnóstico por imagem , Adulto , Idoso , COVID-19/etiologia , Criança , Doenças do Sistema Digestório/etiologia , Feminino , Cardiopatias/etiologia , Humanos , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/etiologia , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/etiologia , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Trombose/diagnóstico por imagem , Trombose/etiologia , Tomografia Computadorizada por Raios X , Doenças Urológicas/etiologia
11.
Nefrología (Madrid) ; 41(2): 154-164, mar.-abr. 2021. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-201568

RESUMO

El incremento de la demanda asistencial por afección renal asociada a enfermedades neoplásicas es una realidad en la mayoría de los servicios de nefrología. Para dar respuesta a esta situación, debe considerarse la creación de modelos asistenciales como consultas monográficas y desarrollar programas de formación en onconefrología que permitan optimizar la atención de estos pacientes. A través de un estudio exploratorio y descriptivo, identificamos cuál es la situación actual de la afectación renal en pacientes con cáncer. El objetivo del presente estudio es establecer los criterios para la asistencia específica en el ámbito de la onconefrología. Para ello hemos revisado aspectos clave y analizado la situación actual en nuestro entorno, mediante una encuesta dirigida a todos los nefrólogos a través de la SEN, junto a la experiencia de 2 centros españoles. A partir de esta información hemos establecido una serie de requisitos y recomendaciones para la puesta en marcha de estas consultas


The increase in demand for medical care for renal complications associated with neoplastic diseases is a reality in most nephrology departments. In response to this overall situation, the creation of healthcare models such as monographic consultations and develop training programs in onconephrology could improve the care of these patients. Through an exploratory and descriptive study, we identified current situation of kidney involvement in cancer patients. The objective of the present study is to establish the criteria for specific assistance in the field of onconephrology. For this, we have reviewed key aspects and analyzed the current situation in our country, through a survey addressed to all nephrologists through the Spanish Society of Nephrology, together with the experience of 2 Spanish centers. From this information, we have established some requirements and recommendations for the start-up of these consultations


Assuntos
Humanos , Neoplasias/complicações , Nefropatias/etiologia , Nefropatias/terapia , Encaminhamento e Consulta/normas , Detecção Precoce de Câncer , Nefropatias/diagnóstico , Neoplasias/terapia , Fatores de Risco , Equipe de Assistência ao Paciente , Inquéritos e Questionários , Nefrologia , Oncologia , Espanha
12.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923686

RESUMO

Currently in Europe, despite the many advances in production technology of synthetic drugs, the interest in natural herbal medicines continues to increase. One of the reasons for their popular use is the assumption that natural equals safe. However, herbal medicines contain pharmacologically active ingredients, some of which have been associated with adverse effects. Kidneys are particularly susceptible to injury induced by toxins, including poisonous constituents from medicinal plants. The most recognized herb-induced kidney injury is aristolochic acid nephropathy connected with misuse of certain Traditional Chinese herbal medicines. Data concerning nephrotoxicity of plant species of European origin are scarce. Here, we critically review significant data of the nephrotoxicity of several plants used in European phytotherapy, including Artemisia herba-alba, Glycyrrhiza glabra, Euphorbia paralias, and Aloe). Causative mechanisms and factors predisposing to intoxications from the use of herbs are discussed. The basic intention of this review is to improve pharmacovigilance of herbal medicine, especially in patients with chronic kidney diseases.


Assuntos
Nefropatias/etiologia , Farmacovigilância , Plantas Medicinais/efeitos adversos , Animais , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/toxicidade , Europa (Continente) , Humanos , Rim/efeitos dos fármacos , Nefropatias/epidemiologia , Plantas Medicinais/toxicidade
13.
BMC Infect Dis ; 21(1): 397, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926392

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) has emerged as a major global health threat with a great number of deaths worldwide. Despite abundant data on that many COVID-19 patients also displayed kidney disease, there is limited information available about the recovery of kidney disease after discharge. METHODS: Retrospective and prospective cohort study to patients with new-onset kidney disease during the COVID-19 hospitalization, admitted between January 28 to February 26, 2020. The median follow-up was 4 months after discharge. The follow-up patients were divided into the recovery group and non-recovery group. Descriptive statistics and between-groups comparison were used. RESULTS: In total, 143 discharged patients with new-onset kidney disease during the COVID-19 hospitalization were included. Patients had a median age was 64 (IQR, 51-70) years, and 59.4% of patients were men. During 4-months median follow-up, 91% (130 of 143) patients recovered from kidney disease, and 9% (13 of 143) patients haven't recovered. The median age of patients in the non-recovery group was 72 years, which was significantly higher than the median age of 62 years in the recovery group. Discharge serum creatinine was significantly higher in the non-recovery group than in the recovery group. CONCLUSIONS: Most of the new-onset kidney diseases during hospitalization of COVID-19 patients recovered 4 months after discharge. We recommend that COVID-19 patients with new-onset kidney disease be followed after discharge to assess kidney recovery, especially elderly patients or patients with high discharge creatinine.


Assuntos
COVID-19/etiologia , Creatinina/sangue , Nefropatias/etiologia , Idoso , Antivirais/uso terapêutico , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/terapia , China/epidemiologia , Comorbidade , Feminino , Seguimentos , Taxa de Filtração Glomerular , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Nefropatias/epidemiologia , Nefropatias/terapia , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Estudos Prospectivos , Proteinúria/epidemiologia , Proteinúria/virologia , Respiração Artificial , Estudos Retrospectivos
14.
FASEB J ; 35(5): e21530, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33813752

RESUMO

Circadian clock is involved in regulating most renal physiological functions, including water and electrolyte balance and blood pressure homeostasis, however, the role of circadian clock in renal pathophysiology remains largely unknown. Here we aimed to investigate the role of Bmal1, a core clock component, in the development of renal fibrosis, the hallmark of pathological features in many renal diseases. The inducible Bmal1 knockout mice (iKO) whose gene deletion occurred in adulthood were used in the study. Analysis of the urinary water, sodium and potassium excretion showed that the iKO mice exhibit abolished diurnal variations. In the model of renal fibrosis induced by unilateral ureteral obstruction, the iKO mice displayed significantly decreased tubulointerstitial fibrosis reflected by attenuated collagen deposition and mitigated expression of fibrotic markers α-SMA and fibronectin. The hedgehog pathway transcriptional effectors Gli1 and Gli2, which have been reported to be involved in the pathogenesis of renal fibrosis, were significantly decreased in the iKO mice. Mechanistically, ChIP assay and luciferase reporter assay revealed that BMAL1 bound to the promoter of and activate the transcription of Gli2, but not Gli1, suggesting that the involvement of Bmal1 in renal fibrosis was possibly mediated via Gli2-dependent mechanisms. Furthermore, treatment with TGF-ß increased Bmal1 in cultured murine proximal tubular cells. Knockdown of Bmal1 abolished, while overexpression of Bmal1 increased, Gli2 and the expression of fibrosis-related genes. Collectively, these results revealed a prominent role of the core clock gene Bmal1 in tubulointerstitial fibrosis. Moreover, we identified Gli2 as a novel target of Bmal1, which may mediate the adverse effect of Bmal1 in obstructive nephropathy.


Assuntos
Fatores de Transcrição ARNTL/fisiologia , Fibrose/prevenção & controle , Regulação da Expressão Gênica , Nefropatias/prevenção & controle , Proteínas Circadianas Period/fisiologia , Proteína Gli2 com Dedos de Zinco/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Gli2 com Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/metabolismo
15.
Transplant Proc ; 53(5): 1562-1569, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33892933

RESUMO

OBJECTIVE: Endothelial disturbance is well known as one of the causes of thrombosis. This study measured von Willebrand factor (vWF) and soluble thrombomodulin (sTM) in renal vein blood to evaluate for the risk of thrombosis after kidney transplantation. METHODS: A cross-sectional study that included 61 consecutive recipients of kidney transplant. The sTM and activity of vWF were evaluated in blood of the renal vein at the time of reperfusion. RESULTS: The renal vein blood had higher values of vWF activity and sTM concentration than the peripheral blood. In the first minutes of reperfusion, the concentration of thrombomodulin was the highest but activity of vWF was the lowest. As the reperfusion continued, thrombomodulin gradually decreased, but vWF increased. The strong correlations of TMs and vWF with warm ischemia were observed (r = 0.5577 and r = 0.3429, respectively). Thrombosis was found in about 10% of all recipients. However, other complications, such as delayed graft function or ureter necrosis, were associated with high values of vWF and sTM. They were correlated with increased sTM concentration and activity of vWF (P < .006 and P < .05, respectively). This was confirmed by analysis of the receiver operator characteristic curve. The area under the curve values for TMs and vWF were 0.762 and 0.602, respectively (P < .0001 and P < .015, respectively). The cutoff points for sTM and vWF were 14.89 ng/mL and 129.89%, respectively. Positive prediction value sTM and vWF were 76% and 66% and negative prediction value 69% and 59%, respectively. CONCLUSIONS: The endothelium of a transplanted kidney could be involved in the pathogenesis of renal thrombosis. Endothelial protection during harvesting can greatly contribute to the improvement of transplantation outcomes. The renal pool of sTM and vWF could be a useful marker of the risk of renal thrombosis.


Assuntos
Nefropatias/etiologia , Complicações Pós-Operatórias/etiologia , Trombomodulina/análise , Trombose/etiologia , Fator de von Willebrand/análise , Adulto , Biomarcadores/sangue , Estudos Transversais , Endotélio Vascular/metabolismo , Feminino , Humanos , Rim/irrigação sanguínea , Nefropatias/sangue , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Período Pré-Operatório , Veias Renais/metabolismo , Medição de Risco , Fatores de Risco , Trombose/sangue
16.
High Blood Press Cardiovasc Prev ; 28(4): 365-372, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33881750

RESUMO

INTRODUCTION: Although multiple home blood pressure variability (HBPV) indices have been proposed, the superiority of one over another is not clear in treated hypertensives. AIM: We evaluated the correlation between different indices of HBPV and hypertension-mediated organ damage (HMOD) in this population and determined predictors of greater HBPV. METHODS: We included adult treated hypertensives who performed an HBP monitoring (duplicate sitting BP readings in the morning, afternoon, and evening for 4 days, Omron HEM-705CP-II), laboratory measurements, transthoracic echocardiogram and carotid-femoral pulse wave velocity. We selected HBPV indices from three different calculation approaches: coefficient of variation (CoV), difference between maximum and minimum BP (MMD), and morning BP increase (MI), and evaluated their correlation with left ventricular mass index, relative wall thickness (RWT), ejection fraction, arterial stiffness and estimated glomerular filtration rate through a correlation matrix. For those variability indices significantly associated with HMOD, we constructed multiple linear regression models to determine independent predictors of HBPV. RESULTS: We included 204 patients, mean age 67.2 (± 13.8) years, 64% female. CoV and MMD for systolic BP showed the greatest correlation with HMOD. Factors independently associated both with CoV and MMD were: older age (b = 0.07; 95% CI 0.04-0.07; p < 0.001 and b = 0.4; 95% CI 0.2-0.5; p < 0.001, respectively), history of stroke (b = 3.6; 95% CI 0.9-6.4; p = 0.01 and b = 25.7; 95% CI 10.1-41.2; p = 0.001, respectively), and body mass index [b = - 0.1; 95% CI - 0.2 to (- 0.02); p = 0.01 and b = - 0.5; 95% CI - 0.9 to (- 0.1); p = 0.01, respectively]. CONCLUSION: CoV and MMD showed the greatest association with HMOD in treated hypertensives. Older age, history of stroke and lower body mass index were easy-to-detect predictors.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea , Hipertensão/diagnóstico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos Transversais , Feminino , Cardiopatias/diagnóstico , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertensão/terapia , Nefropatias/diagnóstico , Nefropatias/etiologia , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia
17.
FASEB J ; 35(5): e21595, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33908676

RESUMO

Current histological measurement techniques for interstitial collagen, the basis of interstitial fibrosis, are semi-quantitative at best and only provide a ratio of collagen levels within tissues. The Genesis200 imaging system and supplemental image analysis software, FibroIndex from HistoIndex, is a novel, automated platform that uses second-harmonic generation (SHG) for imaging and characterization of interstitial collagen deposition and additional characteristics, in the absence of any staining. However, its ability to quantify renal fibrosis requires investigation. This study compared SHG imaging of renal fibrosis in mice with unilateral ureteric obstruction (UUO), to that of Masson's trichrome staining (MTS) and immunohistochemistry (IHC) of collagen I. Additionally, the platform generated data on collagen morphology and distribution patterns. While all three methods determined that UUO-injured mice underwent significantly increased renal fibrosis after 7 days, the HistoIndex platform additionally determined that UUO-injured mice had a significantly increased collagen-to-tissue cross reticulation ratio (all P < .001 vs sham group). Furthermore, in UUO-injured mice treated with the relaxin family peptide receptor-1 agonists, relaxin (0.5 mg/kg/day) or B7-33 (0.25 mg/kg/day), or angiotensin converting enzyme-inhibitor, perindopril (1 mg/kg/day) over the 7-day period, only the HistoIndex platform determined that the drug-induced prevention of renal fibrosis correlated with significantly reduced collagen fiber thickness and collagen-to-tissue cross reticulation ratio, but increased collagen fiber counts. Relaxin or B7-33 treatment also increased renal matrix metalloproteinase-2 and reduced tissue inhibitor of metalloproteinase-1 levels (all P < .01 vs UUO alone). This study demonstrated the diagnostic value of the HistoIndex platform over currently used staining techniques.


Assuntos
Fibrose/patologia , Nefropatias/patologia , Fragmentos de Peptídeos/farmacologia , Relaxina/farmacologia , Obstrução Ureteral/complicações , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Fibrose/tratamento farmacológico , Fibrose/etiologia , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
Int J Mol Sci ; 22(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918699

RESUMO

Renal fibrosis is a complex disorder characterized by the destruction of kidney parenchyma. There is currently no cure for this devastating condition. Extracellular vesicles (EVs) are membranous vesicles released from cells in both physiological and diseased states. Given their fundamental role in transferring biomolecules to recipient cells and their ability to cross biological barriers, EVs have been widely investigated as potential cell-free therapeutic agents. In this review, we provide an overview of EVs, focusing on their functional role in renal fibrosis and signaling messengers responsible for EV-mediated crosstalk between various renal compartments. We explore recent findings regarding the renoprotective effect of EVs and their use as therapeutic agents in renal fibrosis. We also highlight advantages and future perspectives of the therapeutic applications of EVs in renal diseases.


Assuntos
Vesículas Extracelulares/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Animais , Micropartículas Derivadas de Células/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Exossomos/metabolismo , Sangue Fetal/citologia , Fibroblastos/metabolismo , Fibrose , Humanos , Nefropatias/etiologia , Células-Tronco Mesenquimais/metabolismo
19.
Mar Drugs ; 19(4)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810216

RESUMO

Mitochondrial dysfunction contributes to the pathogenesis of kidney injury related with cardiovascular disease. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) protects renal tubular cells by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). AMP-activated protein kinase (pAMPK)-mediated phosphorylation and sirtuin 1/3 (SIRT1/3)-mediated deacetylation are required for PGC-1α activation. In the present study, we aimed to investigate whether omega-3 fatty acids (FAs) regulate the expression of mediators of mitochondrial biogenesis in 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were assigned to the following groups: sham control, Nx, and Nx treated with omega-3 FA. The expression of PGC-1α, phosphorylated PGC-1α (pPGC-1α), acetylated PGC-1α, and factors related to mitochondrial biogenesis was examined through Western blot analysis. Compared to the control group, the expression of PGC-1α, pAMPK, SIRT1/3, Nrf1, mTOR, and Nrf2 was significantly downregulated, and that of Keap 1, acetylated PGC-1α, and FoxO1/3, was significantly upregulated in the Nx group. These changes in protein expression were rescued in the omega-3 FA group. However, the expression of pPGC-1α was similar among the three groups. Omega-3 FAs may involve mitochondrial biogenesis by upregulating Nrf1 and Nrf2. This protective mechanism might be attributed to the increased expression and deacetylation of PGC-1α, which was triggered by SIRT1/3.


Assuntos
Ácidos Graxos Ômega-3/farmacologia , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fator 1 Nuclear Respiratório/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Sirtuínas/metabolismo , Acetilação , Animais , Modelos Animais de Doenças , Rim/enzimologia , Rim/patologia , Nefropatias/enzimologia , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Nefrectomia , Biogênese de Organelas , Processamento de Proteína Pós-Traducional , Ratos Sprague-Dawley , Transdução de Sinais
20.
Indian J Med Microbiol ; 39(2): 262-264, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33781657

RESUMO

As the world fights with the Coronavirus, most of the hospitals are gearing up for the care of these patients. As most of the attention these days is being given on Coronavirus, the patients suffering from other clinical infections are being neglected. SARS-CoV-2 is being kept as the top differential in patients presenting with fever and respiratory distress. We hereby present a case of patient returning from Indonesia during the pandemic presenting with a history of hepatic, renal dysfunction with fever and cough. Due to the pandemic, the patient's fever and cough outweighed the hepatic and renal dysfunction, and the patient had to undergo dialysis before the final diagnosis of leptospirosis could be made.


Assuntos
COVID-19/diagnóstico , Leptospirose/diagnóstico , SARS-CoV-2 , Idoso , Humanos , Nefropatias/etiologia , Hepatopatias/etiologia , Masculino
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