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1.
Cell Physiol Biochem ; 54(1): 88-109, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31990489

RESUMO

Extracellular vesicles (EVs) are important mediators of intercellular communication. Since EVs are also released during pathological conditions, there has been considerable interest in their potential as sensitive biomarkers of cellular stress and/or injury. In the context of kidney disease, urinary EVs are promising indicators of glomerular and tubular damage. In the present review we discuss the role of urinary EVs in kidney health and disease. Our focus is to explore urinary large EVs (lEVs, often referred to as microparticles or microvesicles) as direct and noninvasive early biomarkers of renal injury. In this regard, studies have been demonstrating altered levels of urinary lEVs, especially podocyte-derived lEVs, preceding the decrease of renal function assessed by classical markers. In addition, we discuss the role of small EVs (sEVs, often referred to as exosomes) and their contents in kidney pathophysiology. Even though results concerning the production of sEVs during diseased conditions are varied, there has been a consensus on the importance of urinary sEV content assessment in kidney disease. These mediators, including EV-released miRNAs and mRNAs, are responsible for EV-mediated signaling in the regulation of renal cellular homeostasis, pathogenesis and regeneration. Finally, steps necessary for the validation of EVs as reliable markers will be discussed.


Assuntos
Vesículas Extracelulares/patologia , Nefropatias/diagnóstico , Glomérulos Renais/patologia , Túbulos Renais/patologia , Animais , Biomarcadores/análise , Biomarcadores/urina , Humanos , Nefropatias/patologia , Nefropatias/urina
2.
Toxicol Lett ; 319: 204-212, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760061

RESUMO

Doxorubicin has been indicated to be cardiotoxic and nephrotoxic, and thus it is often used as a model drug. Possible molecular mechanisms of this toxicity have been proposed, however, the systematic investigation of time-related metabolic trajectories specific to renal toxicity has rarely been reported. The present study was designed to assess time-dependent changes in doxorubicin-induced nephropathy through urinary metabolomics and to reveal the molecular mechanism based on key pathways. Urinary metabolomics revealed that the 14th day was the critical time point for model construction. Pathway analysis results showed that 5 pathways with impact (>0.1), FDR (<0.1) and p value (<0.05) were important. Furthermore, three pathways, including butanoate metabolism, alanine, aspartate and glutamate metabolism and arginine and proline metabolism, were focused on and validated by partial least squares regression analysis (PLS-RA) and molecular docking techniques. Our findings also showed that robust metabolomics combined with PLS-RA and molecular docking techniques is promising for elucidating time-dependent changes due to doxorubicin toxicity and for clarifying mechanisms, and the results provide a research foundation for the construction of a nephropathy model.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/urina , Metaboloma/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Rim/patologia , Nefropatias/patologia , Masculino , Metabolômica , Simulação de Acoplamento Molecular , Proteinúria/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
3.
Life Sci ; 241: 117187, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31863776

RESUMO

AIMS: Renal interstitial fibrosis (RIF) is marked by the epithelial-mesenchymal transition (EMT) and excessive extracellular matrix deposition. The long noncoding RNA myocardial infarction-associated transcript (MIAT) facilitates RIF; however, the molecular mechanism of MIAT in RIF remains unclear. Here, we explored the possible underlying mechanisms through which MIAT modulates RIF. MATERIALS AND METHODS: MIAT expression in human renal fibrotic tissues and unilateral ureteral obstruction (UUO) model mice was detected by qPCR. Transforming growth factor ß1 (TGF-ß1) was introduced to stimulate the EMT in human renal proximal tubular epithelial (HK-2) cells. CCK8, EdU, transwell and wound healing assays were employed to measure cell viability, proliferation, and migration respectively. RNA immunoprecipitation (RIP) assays and dual luciferase reporter assays were applied to determine the relationships among MIAT, miR-145, and EIF5A2. KEY FINDINGS: MIAT was upregulated in human renal fibrotic tissues and UUO model mice compared with normal tissue adjacent to renal tumors and sham operation mice, respectively. MIAT knockdown reduced cell viability, proliferation, migration, and the EMT in HK-2 cells. Additionally, MIAT served as an endogenous sponge for miR-145 in the TGF-ß1-induced-EMT in HK-2 cells, as demonstrated by dual luciferase reporter assays and RIP assays. EIF5A2 was confirmed as a target of miR-145, and MIAT knockdown suppressed EIF5A2 expression by sponging miR-145. Downregulation of EIF5A2 partly reversed induction of the EMT by miR-145 inhibitor transfection. SIGNIFICANCE: MIAT promoted cell viability, proliferation, migration, and the EMT via regulation of the miR-145/EIF5A2 axis. These data established a potential therapy for RIF.


Assuntos
Transição Epitelial-Mesenquimal , Fibrose/patologia , Nefropatias/patologia , MicroRNAs/genética , Fatores de Iniciação de Peptídeos/metabolismo , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/metabolismo , Obstrução Ureteral/patologia , Animais , Estudos de Casos e Controles , Fibrose/genética , Fibrose/metabolismo , Regulação da Expressão Gênica , Humanos , Nefropatias/genética , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo
4.
Braz J Med Biol Res ; 52(11): e8772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664306

RESUMO

This study aimed to investigate the mechanism of fluorofenidone (AKF-PD) in treating renal interstitial fibrosis in rats with unilateral urinary obstruction (UUO). Thirty-two male Sprague-Dawley rats were randomly divided into sham, UUO, UUO + enalapril, and UUO + AKF-PD groups. All rats, except sham, underwent left urethral obstruction surgery to establish the animal model. Rats were sacrificed 14 days after surgery, and serum was collected for renal function examination. Kidneys were collected to observe pathological changes. Immunohistochemistry was performed to assess collagen I (Col I) protein expression, and terminal deoxynucleotidyl transferase-mediated nick end-labeling staining to observe the apoptosis of renal tubular epithelial cells. The expression of Fas-associated death domain (FADD), apoptotic protease activating factor-1 (Apaf-1), and C/EBP homologous protein (CHOP) proteins was evaluated by immunohistochemistry and western blot analysis. AKF-PD showed no significant effect on renal function in UUO rats. The pathological changes were alleviated significantly after enalapril or AKF-PD treatment, but with no significant differences between the two groups. Col I protein was overexpressed in the UUO group, which was inhibited by both enalapril and AKF-PD. The number of apoptotic renal tubular epithelial cells was much higher in the UUO group, and AKF-PD significantly inhibited epithelial cells apoptosis. The expression of FADD, Apaf-1, and CHOP proteins was significantly upregulated in the UUO group and downregulated by enalapril and AKF-PD. In conclusion, AKF-PD improved renal interstitial fibrosis by inhibiting apoptosis of renal tubular epithelial cells in rats with UUO.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Nefropatias/patologia , Piridonas/farmacologia , Obstrução Ureteral/patologia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Fator Apoptótico 1 Ativador de Proteases/efeitos dos fármacos , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Nitrogênio da Ureia Sanguínea , Colágeno Tipo I/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Creatinina/sangue , Modelos Animais de Doenças , Enalapril/metabolismo , Enalapril/farmacologia , Proteína de Domínio de Morte Associada a Fas/efeitos dos fármacos , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fibrose , Masculino , Piridonas/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Fator de Transcrição CHOP/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo
5.
Transplant Proc ; 51(9): 2890-2898, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31606185

RESUMO

BACKGROUND: Transplantation of kidneys from donation after cardiocirculatory death (DCD) donors is becoming an ever-increasing reality. So far, biopsy histologic assessment is the main parameter for evaluation of graft suitability, but it has several drawbacks and has poor reliability. The aim of this study is to verify if real-time renal resistance (RR) measurement during hypothermic machine perfusion (HMP) can be used as a reliable parameter to evaluate the quality of grafts from DCD and extracorporeal membrane oxygenation (ECMO) donors. METHODS: From January 2015 to September 2018, HMP has been systematically applied to all organs from DCD and ECMO donors. All grafts underwent preimplantation biopsy histologic assessment with Karpinski's score. Single kidney transplants (SKTs) or double kidney transplants (DKTs) were performed according to biopsy score results. Kidneys were considered suitable for transplant if RR reached ≤ 1.0 within 3 hours of perfusion. RR trend and postoperative outcome were analyzed considering biopsy score and donor type. RESULTS: A total of 30 kidneys (15 from DCD and 15 from ECMO donors) were used to perform 26 transplants (22 SKTs and 4 DKTs). Considering RR trend, all grafts were considered suitable for transplant within 1 hour of perfusion. Biopsy confirmed this result in all cases, and median score was 3 (range, 0-7). SKT score kidneys had lower starting RR than DKT ones (1.88 vs 2.88; P = .04) but identical final RR (0.58 vs 0.57; P = .76). DKT recipients had faster postoperative creatinine reduction than SKT recipients but similar postoperative day 30 value (1.42 vs 1.15 mg/dL; P = .20). No differences were found between DCD and ECMO grafts in terms of RR trend and postoperative outcome. CONCLUSIONS: HMP can be an alternative to histologic biopsy assessment for evaluation of transplant suitability of DCD and ECMO kidneys. If acceptability threshold is reached, SKT can be performed in all cases. ECMO donors should be considered like DCD donors.


Assuntos
Transplante de Rim/métodos , Obtenção de Tecidos e Órgãos/métodos , Transplantes/patologia , Transplantes/provisão & distribução , Biópsia , Oxigenação por Membrana Extracorpórea/métodos , Feminino , Sobrevivência de Enxerto , Humanos , Nefropatias/diagnóstico , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Perfusão/métodos , Projetos Piloto , Fatores de Tempo , Doadores de Tecidos/provisão & distribução , Transplantes/normas
6.
Toxicol Lett ; 317: 110-119, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618666

RESUMO

Trichloroethylene (TCE), a commonly used industrial solvent and degreasing agent, is known to cause trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including skin, liver and kidney. Clinical evidence have shown that the kidney injury occurs in THS and our previous studies suggested that the terminal complement complex C5b-9 deposited in impaired renal tubules induced by TCE with unclear mechanisms. In the present study, we questioned whether activation of the complement system with renal deposition of C5b-9 contributes to TCE-induced kidney injury in THS. We established a BALB/c mouse model of TCE sensitization with or without pretreatment of exogenous CD59, a C5b-9 inhibitory protein. H&E staining, PAS staining, and biochemical detection of urinary proteins were performed to assess renal function. Deposition of C5b-9 and expression of CD59 were evaluated by immunohistochemistry. Sub-lytic effects of C5b-9 in tubular epithelial cells were assessed by lactate dehydrogenase (LDH) cytotoxicity assay. Expression of endocytosis receptors megalin and cubilin on proximal tubules were assessed by immunofluorescence and qRT-PCR. We found that TCE sensitization induced structural and functional changes of renal tubules in mice, associated with the deposition of sub-lytic C5b-9 on proximal tubular epithelial cells. TCE sensitization decreased proximal tubule uptake of filtered proteins and renal expression of megalin and cubilin, phenotypes that were attenuated by pretreatment with exogenous CD59. Overall, our findings reveal a novel mechanism underlying sub-lytic C5b-9 acting on megalin and cubilin, contributes to the renal tubules damage by TCE exposure.


Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Endocitose , Hipersensibilidade/metabolismo , Nefropatias/metabolismo , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Receptores de Superfície Celular/metabolismo , Tricloroetileno , Animais , Células Cultivadas , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Modelos Animais de Doenças , Feminino , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Nefropatias/induzido quimicamente , Nefropatias/imunologia , Nefropatias/patologia , Túbulos Renais Proximais/imunologia , Túbulos Renais Proximais/patologia , Camundongos Endogâmicos BALB C , Transporte Proteico
7.
Molecules ; 24(17)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31480595

RESUMO

Pyrrole-imidazole (PI) polyamides are novel gene silencers that strongly bind the promoter region of target genes in a sequence-specific manner to inhibit gene transcription. We created a PI polyamide targeting human TGF-ß1 (hTGF-ß1). To develop this PI polyamide targeting hTGF-ß1 (Polyamide) as a practical medicine for treating progressive renal diseases, we examined the effects of Polyamide in two common marmoset models of nephropathy. We performed lead optimization of PI polyamides that targeted hTGF-ß1 by inhibiting in a dose-dependent manner the expression of TGF-ß1 mRNA stimulated by PMA in marmoset fibroblasts. Marmosets were housed and fed with a 0.05% NaCl and magnesium diet and treated with cyclosporine A (CsA; 37.5 mg/kg/day, eight weeks) to establish chronic nephropathy. We treated the marmosets with nephropathy with Polyamide (1 mg/kg/week, four weeks). We also established a unilateral urethral obstruction (UUO) model to examine the effects of Polyamide (1 mg/kg/week, four times) in marmosets. Histologically, the renal medulla from CsA-treated marmosets showed cast formation and interstitial fibrosis in the renal medulla. Immunohistochemistry showed strong staining of Polyamide in the renal medulla from CsA-treated marmosets. Polyamide treatment (1 mg/kg/week, four times) reduced hTGF-ß1 staining and urinary protein excretion in CsA-treated marmosets. In UUO kidneys from marmosets, Polyamide reduced the glomerular injury score and tubulointerstitial injury score. Polyamide significantly suppressed hTGF-ß1 and snail mRNA expression in UUO kidneys from the marmosets. Polyamide effectively improved CsA- and UUO-associated nephropathy, indicating its potential application in the prevention of renal fibrosis in progressive renal diseases.


Assuntos
DNA/metabolismo , Imidazóis/farmacologia , Nefropatias/genética , Nylons/farmacologia , Peptídeos/metabolismo , Regiões Promotoras Genéticas , Pirróis/farmacologia , Fator de Crescimento Transformador beta1/genética , Animais , Sequência de Bases , Caderinas/metabolismo , Callithrix , Ciclosporina , Fibrose , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Obstrução Uretral/genética , Obstrução Uretral/patologia
8.
Ann Biol Clin (Paris) ; 77(4): 381-389, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31418699

RESUMO

The SFBC working group aimed to deal with biological tests outside the french nomenclature that may be useful in the context of urinary exploration of metabolism. This section will be divides into three parts: 1) nutritional assessment using urinary urea; 2) metabolic assessment of urolithiasis; 3) exploration of tubulopathies. National and international recommendations support the evaluation of nutritional status from urea measurements in urine and dialysate with the following indications: primary metabolic evaluation of urolithiasis patients, monitoring of protein intake in chronic renal failure stage 3 or stage 5D with residual diuresis. For the management of the urolithiasis disease, biomedical tests recommended by the national and international guidelines are the measurement of the urinary density using refractometry in the primary metabolic evaluation as well as the determination of oxalemia in the diagnosis (patients with GFR< 30 mL/min/1.73 m2) and follow-up (patients with GFR< 60 mL/min/1.73 m2) of primary hyperoxaluria. The determination of the bicarbonaturia is retained for the in depth exploration of urolithiasis and tubular acidosis. The measure of chlore in urine is used to evaluate the volume status during metabolic alkalosis and to calculate the urinary anionic gap during metabolic acidosis.


Assuntos
Metabolismo Energético/fisiologia , Nefropatias/diagnóstico , Avaliação Nutricional , Urinálise/métodos , Urolitíase/diagnóstico , Humanos , Nefropatias/patologia , Nefropatias/urina , Túbulos Renais/patologia , Padrões de Referência , Refratometria/métodos , Refratometria/normas , Urinálise/normas , Urolitíase/urina
9.
Environ Sci Pollut Res Int ; 26(30): 31111-31118, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31456145

RESUMO

The present study was conducted to examine the nephrotoxic effects of heavy metals including lead (Pb), manganese (Mn), arsenic (As), and cadmium (Cd) in diabetic and non-diabetic Wistar rats. Animals were exposed to heavy metals for 30 days, Pb was injected as lead acetate (C4H6O4Pb), Mn was injected as manganese chloride (MnCl2), Cd was injected as cadmium chloride (CdCl2), and As was administered orally to rats in the form of sodium arsenite (AsO2Na). Results showed that metal deposition trends in tissues were Pb > As > Cd > Mn and the urinary metal levels were Pb > Cd > As > Mn. Diabetic metal alone, as well as metal mixture-treated groups, showed decreased urinary metal levels as compared with non-diabetic metal alone and metal mixture-treated groups. Both diabetic- and non-diabetic metal mixture-treated groups revealed an increasing trend of blood urea nitrogen (BUN) and serum creatinine. In addition, heavy metal treatments resulted in elevated malondialdehyde (MDA) levels in the kidney tissue while decreased levels of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GHS) were observed in the kidney tissue in comparison with the control group. The histological analysis of the kidney tissues showed tubular degeneration, fibrosis, and vacuolation as a result of heavy metal exposure. The present study revealed that co-exposure of heavy metals (Pb, Cd, Mn, As) induced more nephrotoxicity as compared with the metal alone treatment. Moreover, diabetic Wistar rats are more prone to kidney damage as a result of heavy metal exposure.


Assuntos
Diabetes Mellitus/patologia , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Metais Pesados/toxicidade , Animais , Catalase/metabolismo , Creatinina/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Malondialdeído/metabolismo , Metais Pesados/farmacocinética , Ratos Wistar , Superóxido Dismutase/metabolismo , Distribuição Tecidual
10.
Medicine (Baltimore) ; 98(34): e16934, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441884

RESUMO

RATIONALE: IgG4-related disease (IgG4-RD) is a systemic chronic inflammatory disorder that can affect almost every organ. IgG4-RD includes IgG4-related kidney disease (IgG4-RKD), but lesions affecting the kidney alone or first are very rare, and a complete understanding is lacking. Computed tomography (CT) and magnetic resonance imaging (MRI) findings can show the typical characteristics of IgG4-RKD and provide information for accurate and rapid diagnosis. PATIENT CONCERNS: We report a case of a 60-year-old woman who was admitted to our hospital for dizziness and instability while walking, her bilateral eyelids were also slightly swollen. She had no medical history. DIAGNOSES: CT and MRI images of the patient revealed multiple local and diffuse patchy lesions in the bilateral renal parenchyma and mass-like tissue in the bilateral renal pelvis, accompanied by right hydronephrosis. A pathological examination of renal samples showed numerous lymphocyte and plasma cell infiltration. Immunohistochemistry demonstrated approximately 50% of the IgG-positive plasma cells to be IgG4+. The serum IgG level was obviously elevated, with both C3and C4 levels were reduced. The patient was diagnosed with IgG4-RKD. INTERVENTIONS: The patient received corticosteroid therapy at another hospital. OUTCOMES: The bilateral kidney lesions were smaller on follow-up CT images. LESSONS: IgG4-RKD exhibits some characteristic imaging features. Despite the relatively low incidence of IgG4-RKD, it should be included in differential diagnoses when images show multiple lesions in kidneys with mild and delayed enhancement and hypointensity on T2WI in middle-aged to elderly patients.


Assuntos
Doença Relacionada a Imunoglobulina G4/diagnóstico por imagem , Nefropatias/diagnóstico por imagem , Feminino , Humanos , Imunoglobulina G/sangue , Doença Relacionada a Imunoglobulina G4/sangue , Doença Relacionada a Imunoglobulina G4/patologia , Nefropatias/sangue , Nefropatias/patologia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
11.
Adv Exp Med Biol ; 1165: 17-36, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399959

RESUMO

With continuing damage, both the indigenous cells of the cortex and medulla, and inflammatory cells are involved in the formation and development of renal fibrosis. Furthermore, interactions among the glomerular, tubular, and interstitial cells contribute to the process by excessive synthesis and decreased degradation of extracellular matrix. The morphology of kidney is different from pathological stages of diseases and changes with various causes. At the end stage of the disease, the kidneys are symmetrically contracted with diffuse granules. Most glomeruli show diffuse fibrosis and hyaline degeneration, and intervening tubules become atrophied. Renal interstitium shows obvious hyperplasia of fibrous tissues with marked infiltration of lymphocytes, mononuclear cells, and plasma cells. The renal arterioles are wall thickening frequently because of hyaline degeneration. Morphologic analysis based on Masson staining of the kidney tissues has been regarded as the golden standard to evaluate the visual fibrosis. However, the present studies have found that the evaluation system has poor repeatability. Several computer-aided image analysis techniques have been used to assess interstitial fibrosis. It is possible that the evaluation of renal fibrosis is carried out by the artificial intelligence renal biopsy pathological diagnosis system in the near future.


Assuntos
Nefropatias/patologia , Rim/patologia , Biópsia , Fibrose , Humanos , Glomérulos Renais/patologia
12.
Adv Exp Med Biol ; 1165: 455-466, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399979

RESUMO

Extracellular vesicles (EVs) are the membrane-surrounded structures released by almost all types of cells. Accumulating evidences have suggested that EVs secretion is enhanced under stress conditions and have been associated with a large wide of cellular physiological and pathological processes. In this part, recent understanding about the generation and biological function of EVs was reviewed. Moreover, the role of EVs in renal inflammation and fibrosis and future challenges of EVs study in kidney disease were discussed.


Assuntos
Vesículas Extracelulares , Nefropatias/patologia , Nefrite/patologia , Fibrose , Humanos , Rim/patologia
13.
Biomed Res Int ; 2019: 4516730, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396529

RESUMO

Background and Objectives: Environmental pollution with the different Aluminum (Al) containing compounds has been increased. Liver and kidney are two vital organs targeted by Al accumulation. The aim of this study was to assess the possible protective and curative effects of Lepidium sativum Linn (LS) against Al-induced impairment of liver and kidney in albino rat and to explore the mechanism behind this effect. Materials and Methods: This experimental animal-based study included fifty albino rats divided into five groups, the control, LS-treated (20 mg/kg), AlCl3-treated (10 mg/kg), AlCl3 then LS, and AlCl3 plus LS-treated, simultaneously for 8 weeks. At the end of the experiment, hepatic and renal functions as well as the biomarkers of antioxidants activities were assessed in the serum. Both liver and kidney were dissected out and histopathologically examined. Results: This study showed that administration of AlCl3 caused a significant (p<0.05) reduction in rats body weight. It significantly increased serum AST, ALT, ALP, bilirubin, urea, and creatinine levels and decreased total protein and albumin. AlCl3 significantly reduced enzymatic (catalase), nonenzymatic (reduced glutathione), and ferric reducing antioxidant power (FRAP) in the serum. Histopathologically, it induced necrosis and degeneration of hepatocytes, glomeruli, and renal tubules. Administration of LS after or along with AlCl3 significantly restored the serum biomarkers of liver and kidney functions to their near-normal levels and had the ability to overcome Al-induced oxidative stress and preserved, to some extent, the normal hepatic and renal structure. The coadministration of LS had a superior effect in alleviating Al-induced changes. Conclusion: Exposure to AlCl3 induced a set of functional and structural changes in the liver and kidney of rats evident through both biochemical and histopathological assessment. The antioxidant activity of LS seeds mediated a protective and curative effect of LS against such changes. Further study through a rigorous clinical trial to prove LS activity on human is recommended.


Assuntos
Cloreto de Alumínio/toxicidade , Doença Hepática Induzida por Substâncias e Drogas , Nefropatias , Lepidium sativum/química , Extratos Vegetais/farmacologia , Alumínio/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/prevenção & controle , Extratos Vegetais/química , Ratos
14.
Transplant Proc ; 51(8): 2814-2822, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31439327

RESUMO

BACKGROUND: α1-Antitrypsin (AAT) is an important protein in the anti-inflammatory response that functions to regulate the activity of serine proteinases. We aimed to evaluate the protective effect of AAT on ischemia-reperfusion injury (IRI) in a mouse model. METHODS: We investigated the effects of AAT in a C57BL/6 mouse model of IRI by dividing them into 4 groups: normal control, sham operated, ischemia-reperfusion (IR), and IR after AAT pretreatment (IR-AAT). In the IR-AAT group, mice were pretreated with AAT (80 mg/kg/d) for 3 days before renal ischemia was induced by clamping the bilateral renal vascular pedicles for 30 minutes. At 24 hours after IRI, biochemistry, histology, inflammatory cytokines, and apoptosis were assayed. RESULTS: Blood urea nitrogen and serum creatinine levels were significantly lower in the IR-AAT group than in the IR group. Neutrophil gelatinase-associated lipocalin and kidney injury molecule 1 protein levels were significantly lower in the IR-AAT group than in the IR group. In addition, there were fewer tubular injuries and less interstitial fibrosis in the IR-AAT group than in the IR group, and the expression levels of transforming growth factor ß, interleukin 1ß, and interleukin 6 were significantly lower in the IR-AAT group than in the IR group. When compared with the IR group, there were fewer terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay-positive cells, lower caspase 3 activity and B-cell lymphoma 2-associated X protein (Bax), and higher B-cell lymphoma 2 (Bcl-2) in the IR-AAT group. CONCLUSIONS: α1-Antitrypsin preserved renal function, attenuated tubular injuries and interstitial fibrosis, and inhibited inflammation and apoptosis after renal IRI. Our results suggest that AAT has protective effects against renal IRI by inhibiting inflammatory and apoptosis pathways.


Assuntos
Nefropatias/prevenção & controle , Rim/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Inibidores de Serino Proteinase/uso terapêutico , alfa 1-Antitripsina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/patologia , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/patologia , Inibidores de Serino Proteinase/farmacologia , alfa 1-Antitripsina/farmacologia
15.
Nutrients ; 11(8)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366015

RESUMO

Advanced glycation end-products (AGEs) are an assorted group of molecules formed through covalent bonds between a reduced sugar and a free amino group of proteins, lipids, and nucleic acids. Glycation alters their structure and function, leading to impaired cell function. They can be originated by physiological processes, when not counterbalanced by detoxification mechanisms, or derive from exogenous sources such as food, cigarette smoke, and air pollution. Their accumulation increases inflammation and oxidative stress through the activation of various mechanisms mainly triggered by binding to their receptors (RAGE). So far, the pathogenic role of AGEs has been evidenced in inflammatory and chronic diseases such as chronic kidney disease, cardiovascular disease, and diabetic nephropathy. This review focuses on the AGE-induced kidney damage, by describing the molecular players involved and investigating its link to the excess of body weight and visceral fat, hallmarks of obesity. Research regarding interventions to reduce AGE accumulation has been of great interest and a nutraceutical approach that would help fighting chronic diseases could be a very useful tool for patients' everyday lives.


Assuntos
Produtos Finais de Glicação Avançada , Nefropatias/etiologia , Obesidade/etiologia , Humanos , Nefropatias/patologia
16.
Clin Appl Thromb Hemost ; 25: 1076029619868535, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392894

RESUMO

Warfarin has been associated with renovascular calcification and worsening renal function, whereas rivaroxaban may provide a degree of renopreservation by decreasing vascular inflammation. We sought to compare rivaroxaban and warfarin's impact on renal decline in patients with nonvalvular atrial fibrillation (NVAF) treated in routine practice. Using US MarketScan claims data from January 2012 to December 2017, we identified patients with NVAF newly initiated on rivaroxaban or warfarin with ≥12 months of continuous insurance coverage prior to initiation. Patients with stage 5 chronic kidney disease (CKD) or receiving hemodialysis at baseline were excluded. Outcomes included rates (events/100 person-years) of hospital or emergency department admission for acute kidney injury (AKI) or progression to stage 5 CKD or need for hemodialysis. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weights based on propensity scores (absolute standardized differences <0.1 achieved for all covariates after adjustment). Patients were followed until an event, anticoagulant discontinuation/switch, insurance disenrollment, or end of data availability. Hazard ratios with 95% confidence intervals (CIs) were estimated using Cox regression. We assessed 36 318 rivaroxaban (19.8% received a dose <20 mg/d) and 36 281 warfarin users. Stages 3 and 4 CKD were present in 5% and 1% of patients at baseline, and proteinuria was present in 2%. Rivaroxaban was associated with a 19% (95% CI = 13%-25%) reduction in the hazard of AKI (rates = 4.91 vs 8.45) and an 18% (95% CI = 9%-26%) reduction in progression to stage 5 CKD or hemodialysis (rates = 2.67 vs 4.12). Rivaroxaban appears associated with lower hazards of undesirable renal end points versus warfarin in patients with NVAF.


Assuntos
Fibrilação Atrial/complicações , Rim/efeitos dos fármacos , Rivaroxabana/uso terapêutico , Lesão Renal Aguda/prevenção & controle , Idoso , Fibrilação Atrial/tratamento farmacológico , Bases de Dados Factuais , Progressão da Doença , Feminino , Humanos , Rim/fisiopatologia , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Diálise Renal , Estudos Retrospectivos , Rivaroxabana/farmacologia , Varfarina/farmacologia , Varfarina/uso terapêutico
17.
Kidney Blood Press Res ; 44(4): 858-869, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31352451

RESUMO

BACKGROUND/AIMS: The term monoclonal gammopathy of renal significance (MGRS) was introduced in 2012 to emphasize kidney lesions in monoclonal gammopathy patients. Bortezomib-based chemotherapy has become the first-line treatment for MGRS. OBJECTIVES: The objective of this study was to investigate whether the strategy of combining chemotherapy with autologous stem cell transplantation (ASCT) could improve prognosis and decrease functional kidney impairment in patients with MGRS. METHODS: We reported the case of a 44-year-old Asian patient who was diagnosed with MGRS and received 5 cycles of Velcade® (a trade name for bortezomib), thalidomide, and dexamethasone therapy (VTD therapy), and subsequently underwent ASCT. In addition, we performed a literature review and summarized the latest advances in the characterization, treatment, and prognosis of MGRS. RESULTS: The patient was diagnosed with light chain deposition disease by renal biopsy. After 5 cycles of VTD therapy, the patient had a very good partial response characterized by the resolution of M-protein (20.2% before treatment vs. 2.5% after treatment), remission of the level of serum free lambda (FLAM; over 80% decline), and normalization of the serum free light chain (sFLC) ratio (κ to λ). He also had a renal response characterized by a decreased serum creatinine level (1.61 vs.1.34 mg/dL) and less severe proteinuria (6.77 g/24 h vs.1.264 g/24 h) after chemotherapy. Importantly, after ASCT, the patient achieved a complete response (CR) characterized by a negative serum immunofixation electrophoresis (IFE) result and a dramatic decrement in FLAM (over 90%). Furthermore, 6 months after ASCT, the patient still remained in stable condition with a negative IFE result, normal sFLC ratio, and low level of serum creatinine (1.31 mg/dL) and proteinuria (0.339 g/24 h). In our retrospective literature analysis, we found that MGRS patient survival time and renal outcome had been markedly improved by current therapies due to the popularization of bortezomib-based chemotherapy and ASCT. CONCLUSIONS: The patient successfully achieved CR after VTD therapy followed by ASCT. However, this treatment is controversial, and a standard therapy recommendation for MGRS has not been established. Bortezomib-based chemotherapy combined with ASCT may have prospects for the treatment of MGRS, but the exact effects of ASCT remain unclear and should be thoroughly investigated.


Assuntos
Bortezomib/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Paraproteinemias/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Nefropatias/patologia , Nefropatias/terapia , Masculino , Paraproteinemias/patologia , Talidomida/uso terapêutico , Transplante Autólogo , Resultado do Tratamento
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