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1.
Biochemistry (Mosc) ; 84(11): 1375-1389, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760924

RESUMO

Mesenchymal stromal cell (MSCs) represent a class of biologics with the prospects for employment as immunomodulatory, tissue-protective, and regenerative therapeutics. In parallel with cellular therapy, cell-free therapy based on MSC-secreted bioactive factors is being actively developed. MSCs secrete a variety of protein, peptide, RNA, and lipid mediators which can be concentrated, frozen, or even lyophilized without loss of activity, which gives them a certain advantage over cellular products requiring liquid nitrogen storage and infrastructure to revive frozen cells. This review (i) describes currently conducted clinical trials of cell-free products containing MSC secretome; (ii) summarizes main approaches to the generation and characterization of conditioned media concentrates and extracellular vesicle isolates; (iii) analyzes a variety of preclinical studies where effectiveness of secretome products has been shown; and (iv) summarizes current knowledge about secretome bioactive components obtained by analysis of in vivo models testing the therapeutic potential of the MSC secretome.


Assuntos
Meios de Cultivo Condicionados/química , Células-Tronco Mesenquimais/metabolismo , Lesão Renal Aguda/patologia , Lesão Renal Aguda/prevenção & controle , Animais , Artrite/patologia , Artrite/prevenção & controle , Células da Medula Óssea/citologia , Meios de Cultivo Condicionados/farmacologia , Avaliação Pré-Clínica de Medicamentos , Exossomos/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Células-Tronco Mesenquimais/citologia
2.
Acta Cir Bras ; 34(6): e201900602, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31432993

RESUMO

PURPOSE: To investigate the role and related mechanisms of miR-106a in sepsis-induced AKI. METHODS: Serum from sepsis and healthy patients was collected, sepsis mouse model was established by cecal ligation and puncture (CLP). TCMK-1 cells were treated with lipopolysaccharide (LPS) and transfected with THBS2-small interfering RNA (siTHBS2), miR-106a inhibitor, miR-106a mimics and their negative controls (NCs). The expression of miR-106a, thrombospondin 2 (THBS2), Bax, cleaved caspase-3 and Bcl-2, cell viability, relative caspase-3 activity and TNF-α, IL-1ß, IL-6 content were respectively detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, Cell Counting Kit-8 (CCK-8) and enzyme linked immunosorbent assay (ELISA). The relationship between miR-106a and THBS2 was confirmed by dual luciferase reporter assay. RESULTS: MiR-106a was up-regulated in serum of sepsis patients, CLP-induced mice models and LPS-induced TCMK-1 cells. LPS reduced cell viability and Bcl-2 expression, and increased caspase-3 activity, Bax expression, the content of TNF-α, IL-1ß, IL-6. THBS2 was a target of miR-106a. The decreases of caspase-3 activity, TNF-α, IL-1ß, IL-6, Bax expression and the increases of cell viability, Bcl-2 expression caused by miR-106a knockdown were reversed when THBS2 silencing in LPS-stimulated TCMK-1 cells. CONCLUSION: MiR-106a aggravated LPS-induced inflammation and apoptosis of TCMK-1 cells via regulating THBS2 expression.


Assuntos
Lesão Renal Aguda/metabolismo , Células Epiteliais/patologia , Rim/citologia , MicroRNAs/metabolismo , Sepse/patologia , Trombospondinas/farmacologia , Lesão Renal Aguda/patologia , Adulto , Animais , Apoptose , Estudos de Casos e Controles , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Sepse/metabolismo , Transfecção
3.
Chem Biol Interact ; 308: 269-278, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31153982

RESUMO

Although cisplatin is an effective anticancer drug, its clinical application is limited due to various side effects, especially nephrotoxicity. In this study, we investigated the protective effects and possible mechanisms of hesperetin on cisplatin-induced kidney damage. In vitro, hesperetin significantly attenuated oxidative stress-induced apoptosis by reducing ROS levels in cisplatin-treated HK-2 cells. Simultaneously, hesperetin activated the Nrf2 signaling pathway and regulated its downstream genes, including NQO1 and HO-1. In vivo, hesperetin could significantly attenuate cisplatin-induced nephrotoxicity, blood urea nitrogen (BUN) and serum creatinine (SCr). Furthermore, hesperetin clarifies cisplatin-induced oxidative stress by reducing MDA/MPO levels and increasing SOD/GSH levels. In addition, from the histopathological analysis of the kidney, hesperetin significantly reduced the nephrotoxicity caused by cisplatin compared with the cisplatin group. Moreover, western blotting of renal tissue revealed that hesperetin activates Nrf2 in a dose-dependent manner, attenuates the MAPK signaling pathway against inflammation, and inhibits the expression of apoptotic proteins to protect kidneys from AKI caused by cisplatin. Altogether, these findings suggest that hesperetin may be a potential protectant against cisplatin-induced nephrotoxicity.


Assuntos
Lesão Renal Aguda/patologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Hesperidina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Animais , Antioxidantes/metabolismo , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Creatinina/sangue , Hesperidina/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/patologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Mol Med Rep ; 19(6): 5115-5122, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059037

RESUMO

3,3'­Diindolylmethane (DIM) is a naturally derived indole compound found in the Brassica family of vegetables. DIM has several beneficial effects, including anti­cancer, anti­inflammatory and anti­angiogenic functions. However, the effects of DIM on acute kidney injury (AKI) stimulated by lipopolysaccharide (LPS) are poorly studied. In this present study, male BALB/c mouse models of AKI were established using intraperitoneal injections of 10 mg/kg LPS. DIM (40 mg/kg) was administered intraperitoneally 24 and 2 h before LPS exposure. The results indicated that DIM significantly mitigated histopathological changes in the kidneys and improved the levels of blood urea nitrogen and serum creatinine. DIM also suppressed the LPS­induced production of reactive oxygen species and cell apoptosis. Furthermore, DIM treatment significantly decreased the expression of NADPH oxidase 2 (NOX2) and NOX4 in LPS­treated mice. Therefore, DIM may exert its renoprotective actions by inhibiting NOX­mediated oxidative stress and the apoptosis of renal tubular epithelial cells.


Assuntos
Lesão Renal Aguda/prevenção & controle , Apoptose/efeitos dos fármacos , Indóis/farmacologia , Lipopolissacarídeos/toxicidade , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Regulação para Baixo/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glutationa/metabolismo , Rim/patologia , Túbulos Renais/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NADPH Oxidases/genética , Espécies Reativas de Oxigênio/metabolismo
5.
Nat Commun ; 10(1): 2024, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048699

RESUMO

Mutations in the polycystins cause autosomal dominant polycystic kidney disease (ADPKD). Here we show that transmembrane protein 33 (TMEM33) interacts with the ion channel polycystin-2 (PC2) at the endoplasmic reticulum (ER) membrane, enhancing its opening over the whole physiological calcium range in ER liposomes fused to planar bilayers. Consequently, TMEM33 reduces intracellular calcium content in a PC2-dependent manner, impairs lysosomal calcium refilling, causes cathepsins translocation, inhibition of autophagic flux upon ER stress, as well as sensitization to apoptosis. Invalidation of TMEM33 in the mouse exerts a potent protection against renal ER stress. By contrast, TMEM33 does not influence pkd2-dependent renal cystogenesis in the zebrafish. Together, our results identify a key role for TMEM33 in the regulation of intracellular calcium homeostasis of renal proximal convoluted tubule cells and establish a causal link between TMEM33 and acute kidney injury.


Assuntos
Lesão Renal Aguda/patologia , Cálcio/metabolismo , Túbulos Renais Proximais/metabolismo , Proteínas de Membrana/metabolismo , Canais de Cátion TRPP/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Lesão Renal Aguda/genética , Animais , Membrana Celular/metabolismo , Modelos Animais de Doenças , Embrião não Mamífero , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Túbulos Renais Proximais/citologia , Lisossomos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Knockout , Mutação , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/patologia , RNA Interferente Pequeno/metabolismo , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/fisiologia , Peixe-Zebra , Proteínas de Peixe-Zebra/fisiologia
6.
Cell Physiol Biochem ; 52(6): 1463-1483, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31099507

RESUMO

BACKGROUND/AIMS: The therapeutic potential of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) in kidney injury has been largely reported. However, new approaches are necessary to optimize the efficacy in the treatment of renal diseases. MSCs physiologically are under a low O2 partial pressure (pO2), and culturing adipose-derived MSCs (ADMSCs) in hypoxia alters their secretory paracrine properties. The aim of this study was to evaluate whether hypoxia preconditioning of ADMSCs alters the properties of secreted EVs to improve renal recovery after ischemia-reperfusion injury (IRI). METHODS: The supernatants of ADMSCs cultivated under 21% pO2 (control) or 1% pO2 (hypoxia) were ultracentrifuged for EVs isolation that were posteriorly characterized by flow cytometry and electron microscopy. The uptake and effects of these EVs were analyzed by using in vitro and in vivo models. HK-2 renal tubule cell line was submitted do ATP depletion injury model. Proteomic analyses of these cells treated with EVs after injury were performed by nano-UPLC tandem nano-ESI-HDMSE method. For in vivo analyses, male Wistar rats were submitted to 45 min bilateral ischemia, followed by renal intracapsular administration of ADMSC-EVs within a 72 h reperfusion period. Histological, immunohistochemical and qRT-PCR analysis of these kidneys were performed to evaluate cell death, inflammation and oxidative stress. Kidney function was evaluated by measuring the blood levels of creatinine and urea. RESULTS: The results demonstrate that hypoxia increases the ADMSCs capacity to secrete EVs that trigger different energy supply, antiapoptotic, immunomodulatory, angiogenic and anti-oxidative stress responses in renal tissue compared with EVs secreted in normoxia. Proteomic analyses of renal tubule cells treated with EVs from ADMSCs in normoxia and hypoxia give a specific signature of modulated proteins for each type of EVs, indicating regulation of distinct biological processes. CONCLUSION: In summary, hypoxia potentially offers an interesting strategy to enhance the properties of EVs in the treatment of acute kidney disease.


Assuntos
Lesão Renal Aguda/terapia , Vesículas Extracelulares/transplante , Células-Tronco Mesenquimais/metabolismo , Traumatismo por Reperfusão/terapia , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Tecido Adiposo/citologia , Animais , Hipóxia Celular , Linhagem Celular , Células Cultivadas , Vesículas Extracelulares/metabolismo , Humanos , Rim/metabolismo , Rim/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Células-Tronco Mesenquimais/citologia , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
7.
Eur Cytokine Netw ; 30(1): 34-38, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074416

RESUMO

This study mainly to explore the change of serum cytokines in wasp sting patients and the potential correlation between cytokines and acute kidney injury (AKI) due to wasp stings. The levels of IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ in 33 wasp sting and 24 healthy people were measured by flow cytometry, the level of IL-17 was detected by enzyme-linked immunosorbent assay and the laboratory examination including inflammatory indicators, muscle enzyme markers, and renal function were detected by automatic biochemical analyzer, blood analyzer, and urine analyzer. The wasp sting patients were divided into AKI (n = 10) and non-AKI groups (n = 23). The correlation between the levels of serum cytokines and laboratory examination results was analyzed. The levels of IL-2, IL-6, IL-10, IFN-γ, and IL-17 were statistically increased in wasp sting patients compared with the controls (P < 0.05). IL-6, IL-10, and IL-17 levels were markedly increased in the AKI group compared with the non-AKI group (P < 0.05). Moreover, compared with non-AKI group, inflammatory markers and muscle enzyme markers were more abnormal in the AKI group. The positive rate of urinary occult blood in the AKI group was higher than that in the non-AKI group. The levels of IL-2, IL-4, IL-6, IFN-γ, and IL-17 correlated positively with white blood cell counts. The levels of IL-2, IL-4, IL-10, IFN-γ, and IL-17 correlated positively with the levels of serum creatinine. The levels of IL-2, IL-4, IL-10, IL-10, and IFN-γ correlated positively with the levels of C-reactive protein. The levels of IL-10, and IFN-γ correlated positively with urinary occult blood. Conclusion: Elevated levels of cytokines in wasp sting patients might be involved in the development and progression of acute kidney injury.


Assuntos
Lesão Renal Aguda/sangue , Proteína C-Reativa/análise , Creatinina/sangue , Citocinas/sangue , Mordeduras e Picadas de Insetos/sangue , Lesão Renal Aguda/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-2/sangue , Interleucina-4/sangue , Interleucina-6/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/enzimologia , Sangue Oculto , Fator de Necrose Tumoral alfa/sangue , Vespas/patogenicidade , Adulto Jovem
8.
Chem Biol Interact ; 308: 137-146, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31103702

RESUMO

Cisplatin, a platinum chemotherapeutic agent, is used in a diversity of malignancies; nevertheless, the excessive nephrotoxicity following cisplatin treatment is the dose-limiting devastating reaction. This study was designed to explore the possible nephroprotective impact of wogonin, a forceful anti-oxidant, anti-inflammatory, and anti-tumor agent, in a rat model of cisplatin-induced renal injury. The potential nephroprotective mechanisms were additionally investigated. Wogonin was given at a dose of 40 mg/kg. Acute nephrotoxicity was indicated by a significant rise in BUN, and serum creatinine levels in cisplatin-injected rats. Also, cisplatin enhanced the lipid peroxidation, diminished GSH, catalase, and PPAR-γ levels. Additionally, cisplatin-injected rats showed a significant rise in tissue levels of IL-1ß, TNF-α, NF-kB, and caspase-3 enzymatic activity. Notably, the pre-treatment with wogonin ameliorated the nephrotoxicity indices, oxidative stress, inflammation, and apoptosis induced by cisplatin. Also, wogonin up-regulated PPAR-γ expression. The involvement of Wnt/ß-catenin pathway was debatable; however, our findings showed that it was significantly induced by cisplatin. Wogonin pre-treatment markedly attenuated Wnt/ß-catenin pathway. Collectively, these findings imply that wogonin is a promising nephroprotective agent that improves the therapeutic index of cisplatin via reducing oxidative stress, inflammation as well as inducing PPAR-γ. Also, Wnt/ß-catenin pathway is partially involved in the pathogenesis of cisplatin nephrotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/toxicidade , Flavanonas/farmacologia , PPAR gama/metabolismo , Substâncias Protetoras/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/patologia , Animais , Flavanonas/uso terapêutico , Glutationa/metabolismo , Inflamação/prevenção & controle , Interleucina-1beta/análise , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/análise , Regulação para Cima/efeitos dos fármacos
9.
Curr Protein Pept Sci ; 20(8): 770-776, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31060484

RESUMO

Acute kidney injury (AKI) is a systemic disease characterized by acute loss of renal function and accumulation of end products of nitrogen metabolism. Ischemic AKI is the most common cause of AKI, and inflammatory responses are inevitablely involved in ischemic AKI. In the process of ischemic AKI, multiple factors are involved in activating and recruitment of immune cell to the injured kidney. These factors include DAMPs and HIFs released from the injured kidney, increased expression of adhesion molecules, the production of chemokines and cytokines, activation of complement system and TLRs as well as the permeability dysfunction of the renal vascular endothelium. Immune cells of both the innate and adaptive immune systems, such as neutrophils, dendritic cells, macrophages and lymphocytes contribute to the pathogenesis of renal injury after ischemia reperfusion injury (IRI), with some of their subpopulations also participating in the repair process. Numerous studies of immune cells involved in the pathogenesis of AKI have enhanced the understanding of their possible mechanisms in AKI which might become the potential targets for the treatment of ischemic AKI. This review describes the function of the immune cells in the pathogenesis and repair of ischemic AKI and emphasizes the treatment of ischemic AKI potentially targeting them.


Assuntos
Lesão Renal Aguda/imunologia , Lesão Renal Aguda/patologia , Isquemia/metabolismo , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Imunidade Adaptativa , Animais , Humanos , Imunidade Celular
10.
Inflamm Res ; 68(6): 511-523, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31037316

RESUMO

OBJECTIVE: Chicoric acid (CA) is a natural product with promising antioxidant and anti-inflammatory properties; however, its protective effect on methotrexate (MTX)-induced acute kidney injury (AKI) hasn't been reported. We investigated the effect of CA on MTX-induced AKI in rats, pointing to the role of NF-κB/NLRP3 inflammasome and Nrf2/ARE/HO-1 signaling. MATERIALS AND METHODS: Wistar rats received 25 mg/kg and 50 mg/kg CA for 15 days and a single injection of MTX at day 16. At day 19, the rats were killed, and samples were collected for analyses. RESULTS: MTX induced a significant increase in serum creatinine and urea, and kidney Kim-1, reactive oxygen species (ROS), malondialdehyde and nitric oxide levels. In addition, MTX-induced rats exhibited multiple histopathological alterations, diminished antioxidant defenses, and decreased expression of Nrf2, NQO-1 and HO-1. CA prevented histological alterations, ameliorated kidney function markers, attenuated ROS production and lipid peroxidation, and boosted antioxidant defenses. CA suppressed the expression of NF-κB p65, NLRP3, caspase-1 and IL-1ß in the kidney of MTX-induced rats. Furthermore, CA inhibited MTX-induced apoptosis as evidenced by the decreased expression of BAX and caspase-3, and increased Bcl-2 gene expression. CONCLUSIONS: CA prevented MTX-induced AKI through activation of Nrf2/ARE/HO-1 signaling, and attenuation of ROS-induced activation of NF-κB/NLRP3 inflammasome signaling.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/imunologia , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , Succinatos/farmacologia , Succinatos/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Elementos de Resposta Antioxidante/imunologia , Apoptose/efeitos dos fármacos , Antagonistas do Ácido Fólico , Heme Oxigenase (Desciclizante)/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Masculino , Metotrexato , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ratos Wistar , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
11.
Food Chem Toxicol ; 129: 201-210, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31039387

RESUMO

This study investigated the protective effects of melatonin (MT) against cisplatin (CP)-induced acute kidney injury in rats as well as its possible mechanism of action associated with anti-aging protein Klotho. The following four experimental groups were evaluated: vehicle control, CP (7 mg/kg), CP&MT20 (20 mg/kg/day), and CP&MT40 (40 mg/kg/day). The concomitant administration of MT significantly ameliorated CP-induced acute kidney injury in rats, as evidenced by increased kidney weight, increased serum levels of blood urea nitrogen and creatinine, and increased incidence of histopathological alterations with renal tubular cell apoptosis. In addition, MT treatment protected kidney tissue against oxidative damages and significantly upregulated the expression level of Klotho decreased by CP treatment, resulting in reduced phosphorylation of protein kinase B (AKT) and forkhead box O (FOXO) as well as reduced expression levels of B-cell lymphoma 2-associated X protein (Bax) and caspase-3. MT not only partially regulated oxidative stress via AKT/FOXO signaling, but also reduced apoptosis caused by CP by inhibiting the Bax/caspase-3 pathway. Our results indicated that MT could prevent acute kidney injury induced by CP in rats, presumably through upregulating the expression of Klotho, resulting in elevated anti-oxidant and anti-apoptotic properties.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/prevenção & controle , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Melatonina/farmacologia , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose/fisiologia , Peso Corporal/efeitos dos fármacos , Caspase 3/metabolismo , Glucuronidase/metabolismo , Glucuronidase/fisiologia , Glutationa/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Malondialdeído/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
12.
Biol Res ; 52(1): 29, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31084615

RESUMO

BACKGROUND: Acute kidney injury (AKI), which is mainly caused by sepsis, has high morbidity and mortality rates. CXCL8(3-72) K11R/G31P (G31P) can exert therapeutic effect on inflammatory diseases and malignancies. We aimed to investigate the effect and mechanism of G31P on septic AKI. METHODS: An AKI mouse model was established, and kidney injury was assessed by histological analysis. The contents of serum creatinine (SCr) and blood urea nitrogen (BUN) were measured by commercial kits, whereas neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) were detected by enzyme-linked immunosorbent assay (ELISA) kits. The expressions of CXCL8 in serum and kidney tissues were determined using ELISA and immunohistochemical analysis, respectively. Apoptosis rate of renal tissue was detected by terminal deoxynucleotidyl transfer-mediated dUTP nick end labeling (TUNEL) analysis. The expressions of inflammatory cytokines were measured by quantitative real-time PCR and Western blot, respectively. The apoptosis-related proteins, JAK2, STAT3, NF-κB and IκB were determined by Western blot. RESULTS: G31P could reduce the levels of SCr, BUN, HGAL and KIM-1 and inhibit the renal tissue injury in AKI mice. G31P was also found to suppress the serum and nephric CXCL8 expressions and attenuated the apoptosis rate. The levels of inflammatory cytokines, pro-apoptotic proteins were decreased, while the anti-apoptotic proteins were increased by G31P in AKI mice. G31P also inhibited the activation of JAK2, STAT3 and NF-κB in AKI mice. CONCLUSION: These results suggest that G31P could protect renal function and attenuate the septic AKI. Our findings provide a potential target for the treatment of AKI.


Assuntos
Lesão Renal Aguda/etiologia , Janus Quinase 2/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Sepse/complicações , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/patologia , Transdução de Sinais
13.
Biomed Pharmacother ; 112: 108681, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970510

RESUMO

Acute kidney injury (AKI) is a significant medical problem worldwide. Ischemia-reperfusion (I/R) injury of the kidney is a major cause of AKI. However, the pathogenesis that contributes to renal I/R injury is still unclear. Apoptosis repressor with caspase recruitment domain (ARC) is abundantly expressed in various tissues, and has been reported to play a strong protective role during pathological processes. Our results indicated that ARC expression was decreased in the reperfused kidneys. ARC deficiency markedly accelerated renal dysfunction, promoted reperfusion-regulated tubular epithelial cell apoptosis, and enhanced the vulnerability of kidney to I/R damage. Furthermore, in the kidney samples of mice underwent renal I/R injury, ARC knockout significantly accelerated the expression levels of inflammatory factors, including interleukin (IL)-1ß, IL-6, tumor necrosis factor a (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and IL-2. In addition, renal I/R injury-induced apoptosis was further exacerbated in ARC-deficient mice through promoting the expression of cleaved Caspase-3 and poly (ADP-ribose) polymerase (PARP). From the molecular level, ARC deletion obviously accelerated mitochondrial injury, as evidenced by the further decreased adenosine triphosphate (ATP) levels and mitochondrial potential in hypoxia-reoxygenation (H/R)-treated cells. Moreover, ARC knockout exacerbated AKI through activating phosphorylated protein kinase B (AKT), mammalian target of Rapamycin (mTOR) and p53, whereas reducing phosphorylated glycogen synthase kinase 3ß (GSK3ß). Of note, blocking AKT/mTOR signaling markedly attenuated inflammation, mitochondrial damage and apoptosis stimulated by H/R in ARC knockdown cells. In summary, our results suggested that ARC played a pivotal role in the pathogenesis of AKI induced by renal I/R operation through regulating AKT/mTOR signaling.


Assuntos
Lesão Renal Aguda/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Rim/metabolismo , Proteínas Musculares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/patologia , Animais , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular , Sobrevivência Celular , Citocinas/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Inflamação , Rim/imunologia , Rim/patologia , Túbulos Renais Proximais/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Musculares/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais
14.
Mar Drugs ; 17(4)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991714

RESUMO

In the study, the protective effect of plasma protein from Tachypleus tridentatus (PPTT) on acute kidney injury (AKI) and the related molecular mechanisms were first investigated by Western blotting analyses, TdT-mediated dUTP Nick-End Labeling (TUNEL) assay, and immunohistochemistry. It was found that PPTT had an obviously inhibitory effect on Reactive oxygen species (ROS) in cyclophosphamide (CTX)-exposed mice. Furthermore, results demonstrated that the renal cell death mode is due to inducing apoptosis and autophagy inhibited by dose-dependent PPTT in mice treated with CTX by decreasing the protein expression of bax, beclin-1, and LC3 and increasing the expression of bcl-2. Moreover, the p38 MAPK and PI3K/Akt signaling pathways were observed to take part in the PPTT-induced renal cell growth effect by enhancing the upregulation of the expression of Akt and p-Akt as well as the downregulation of the expression of p38 and p-p38, which indicated a PPTT ameliorating effect on AKI CTX-induced in mice through p38 MAPK and PI3K/Akt signaling pathways. Briefly, this article preliminarily studies the mechanism of the PPTT ameliorating effect on AKI CTX-induced in mice, which helps to provide a reference for PPTT clinical application in AKI therapy.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Proteínas Sanguíneas/farmacologia , Caranguejos Ferradura/química , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Proteínas Sanguíneas/isolamento & purificação , Ciclofosfamida/farmacologia , Modelos Animais de Doenças , Feminino , Caranguejos Ferradura/metabolismo , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Chem Biol Interact ; 306: 47-53, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30974099

RESUMO

Necroptosis is suggested to have an important role in the pathogenesis of rhabdomyolysis induced acute kidney injury (AKI). In this study, the renoprotective effect of diacerein on glycerol-induced AKI was investigated. Twenty four male albino rats were included in this study and divided into four groups: (group I) saline control group, (group II) glycerol-treated group, (groups III&IV) diacerein + glycerol -treated groups (25 and 50 mg/kg/day) respectively. Renal malondialdehyde (MDA) level in addition to catalase and heme oxygenase (HO) activities were estimated. Comet assay and histopathological changes were evaluated. The levels of pro-apoptotic Bcl-2-associated X (Bax) protein, tumor necrosis factor alpha (TNF-α) and receptor-interacting serine/threonine-protein kinases 3 (RIPK3) were measured by ELISA. RIPK3 and mixed lineage kinase domain-like pseudokinase (MLKL) mRNA expression were assessed by real time PCR. Glycerol treatment caused significant renal histological abnormalities and functional impairment (increased urea and creatinine). Increased levels of renal MDA with concomitant decrease in renal catalase activity and significant DNA damage in comet assay were observed. High expression of RIPK3 and MLKL in the glycerol-treated group with marked elevation of Bax, TNF-α and RIPK3 levels and HO-1 activity were also documented. Diacerein treatment dependently attenuated glycerol induced structural and functional changes in kidney and significantly elicit reduction of renal tissue oxidative damage whereas it decreased renal expression of RIPK3 and MLKL, and decreased Bax, TNF-α and RIPK3 levels and HO-1 activity. CONCLUSION: These results demonstrated that diacerein might have potential application in the amelioration of AKI via its anti-oxidant, anti-inflammatory, anti-apoptotic and anti-necroptotic effects.


Assuntos
Lesão Renal Aguda/prevenção & controle , Antraquinonas/farmacologia , Apoptose/efeitos dos fármacos , Glicerol/farmacologia , Inflamação/prevenção & controle , Necrose/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Dano ao DNA/efeitos dos fármacos , Glicerol/administração & dosagem , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Necrose/induzido quimicamente , Necrose/patologia , Ratos , Ratos Wistar
16.
Ren Fail ; 41(1): 314-325, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30991873

RESUMO

Drug dosing adjustment in sepsis-induced acute kidney injury (sepsis-AKI) is currently adjusted based on renal function. Sepsis is a multiorgan injury, and thus, drug metabolism in sepsis-AKI might be interfered by non-renal factors such as changes in functions of drug-metabolizing enzymes in the liver and functions of intestinal drug transporters. We compared the defect on mouse CYP3A11 (human CYP3A4 representative) in liver and intestine along with several intestinal drug transporters (MDR1a, MRP2, and OATP3) in three mouse models; chronic ischemic reperfusion injury (Chr I/R; 4-week), acute ischemic reperfusion injury (Acute I/R; 24-h), and cecal ligation and puncture (CLP; 24-h) as representative of sepsis-AKI. Decreased expression of CYP3A11 and drug transporters was demonstrated in all models. Among these models, sepsis-AKI had the least severe renal injury (increased BUN and Scr) with the most severe liver injury (increased ALT and changes in liver histopathology), the most severe intestinal leakage (increased serum (1→3)-ß-D-glucan) and the highest increase in serum IL-6. A reduced expression and activity of liver and intestinal CYP3A11 along with intestinal efflux-drug transporter expressions (MDR1a and MRP2), but not drug uptake transporter (OATP3), was predominant in sepsis-AKI compared with acute I/R. Additionally, a reduction of CYP3A4 expression with IL-6 was demonstrated on HepG2 cells implying a direct injury of IL-6 on human liver cells. Differences in drug metabolism were reported between sepsis-AKI and ischemic-AKI confirming that drug dosing adjustment in sepsis-AKI depends not just only on renal function but also on several non-renal factors. Further studies are warranted.


Assuntos
Lesão Renal Aguda/patologia , Insuficiência Renal Crônica/patologia , Traumatismo por Reperfusão/patologia , Sepse/complicações , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Lesão Renal Aguda/etiologia , Animais , Quimiocinas CC/metabolismo , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Células Hep G2 , Humanos , Interleucina-6/metabolismo , Intestinos/patologia , Fígado/patologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Transportadores de Ânions Orgânicos/metabolismo , Insuficiência Renal Crônica/etiologia , Traumatismo por Reperfusão/etiologia
17.
Ren Fail ; 41(1): 278-283, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31014141

RESUMO

OBJECTIVE: In the current study, we investigated the incidence of acute kidney injury (AKI) induced by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) and whether such an AKI can recover spontaneously in rats. METHODS: We used transesophageal alternating current stimulation to establish 7 min of CA rat model followed by conventional CPR. The experimental rats were randomly divided into three groups (n = 20 per group) according to the different time points after restoration spontaneous circulation (ROSC): the ROSC 24 h, ROSC 48 h, and ROSC 72 h group. The diagnosis of rat AKI refers to the 2012 KDIGO adult AKI diagnostic criteria. The severity of AKI quantified by the serum creatinine (SCR), blood urea nitrogen (BUN) levels and histological features of renal tissue. RESULTS: The incidence rates of AKI in ROSC 24 h, ROSC 48 h, and ROSC 72 h group were 65%, 45%, and 42.9%. Moreover, the values of SCR and BUN were highest at ROSC 24 h, and then gradually decreased with the time of ROSC. The histological changes of the renal tissues such as glomerular collapse, renal tubular cell swelling, and inflammatory cell infiltration had also observed. CONCLUSION: The incidence of AKI in rats was high after suffering from CA and CPR, but renal function improved with the prolongation of ROSC time, indicating the ability of the kidney to self-repair.


Assuntos
Lesão Renal Aguda/epidemiologia , Reanimação Cardiopulmonar/efeitos adversos , Parada Cardíaca/terapia , Lesão Renal Aguda/sangue , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Animais , Nitrogênio da Ureia Sanguínea , Reanimação Cardiopulmonar/métodos , Creatinina/sangue , Modelos Animais de Doenças , Parada Cardíaca/complicações , Humanos , Incidência , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
18.
Medicine (Baltimore) ; 98(15): e15214, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985721

RESUMO

RATIONALE: Reports of acute kidney injury (AKI) associated with benzbromarone use in patients with hyperuricemia (HUA) are rare so far. PATIENT CONCERNS: We describe 2 unique clinical patterns in which benzbromarone was a possible cause of AKI following self-medication for HUA. In case 1, a 45-year-old man developed AKI after taking 100 mg of benzbromarone. His serum creatinine (Scr) increased to 2.3 mg/dL on day 2 after benzbromarone administration. Ultrasound showed multiple small stones in both kidneys, and the 24-hour urine uric acid level was 3128 mg. In case 2, a 17-year-old male student presented with AKI after self-administration of 50 mg of benzbromarone. His Scr increased to 6.8 mg/dL on day 3 after benzbromarone administration. Ultrasound showed multiple stones in the left kidney. DIAGNOSIS: Both patients underwent renal biopsy, with findings of acute tubular interstitial nephropathy in case 1 and acute tubular damage in case 2. Drug-induced AKI was considered. INTERVENTIONS: Both cases were treated supportively with intravenous hydration only. In both patients, the Scr level recovered within 0.5 months and renal function was normal 3 months after discharge. LESSONS: Oral benzbromarone is widely used in Asian counties to treat HUA and the adverse effects are mostly mild. However, clinicians should be alert for benzbromarone-induced AKI. Moreover, uricosuric drugs should only be used after exclusion of urolithiasis and other contraindications.


Assuntos
Lesão Renal Aguda/etiologia , Benzobromarona/efeitos adversos , Hiperuricemia/tratamento farmacológico , Uricosúricos/efeitos adversos , Urolitíase/tratamento farmacológico , Lesão Renal Aguda/patologia , Adolescente , Benzobromarona/uso terapêutico , Humanos , Hiperuricemia/complicações , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Automedicação/efeitos adversos , Uricosúricos/uso terapêutico , Urolitíase/complicações
19.
Ren Fail ; 41(1): 190-196, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30942115

RESUMO

AIM: Exertional heastroke (EHS) can lead to acute kidney injury. Oral rehydration solution III (ORS III), recommended by WHO in 2004, is used to rehydrate children with gastroenteritis. This study aimed to characterize the renoprotective effect of ORS III in EHS rats. METHODS: Rats were randomly divided into Group Control, Group EHS, Group EHS + Water, and Group EHS + ORS. Thirty minutes before the experiment, ORS III was orally administrated to Group EHS + ORS, Water was given to Group EHS + Water. Rats from Group EHS, Group EHS + Water and Group EHS + ORS were then forced to run until they fatigued. Core temperature (Tc) was monitored and 40.5 °C was considered as the onset of heatstroke. Serum creatinine (SCr), blood urea nitrogen (BUN) were measured using an automated biochemical analyzer. Serum neutrophil gelatinase-associated lipocalin (NGAL) was measured using an NGAL ELISA Kit. Light microscopy was used for kidney structural analysis. RESULTS: SCr level in Group EHS was no different from Group Control (p > .05), while BUN and NGAL levels in Group EHS were higher than Group Control (p <.001, p < .001). SCr, BUN and NGAL concentrations in group EHS + Water were no different from Group EHS (p > .05). SCr, BUN levels in Group EHS + ORS were no different from Group EHS (p > .05). But NGAL levels were significant in these two groups (p = .012). Renal histopathologies of rats in Group EHS and Group EHS + Water showed flattened lumens filled with eosinophilic materials. The damage was milder in Group EHS + ORS, in which injured tubules showed degeneration of the tubular epithelium and sloughing of the brush border membrane. CONCLUSION: ORS III could alleviate the kidney injury in EHS rats.


Assuntos
Lesão Renal Aguda/prevenção & controle , Golpe de Calor/complicações , Temperatura Alta/efeitos adversos , Substâncias Protetoras/uso terapêutico , Soluções para Reidratação/uso terapêutico , Lesão Renal Aguda/sangue , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Proteínas da Fase Aguda , Administração Oral , Animais , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Golpe de Calor/sangue , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Lipocalinas/sangue , Masculino , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas/sangue , Ratos , Ratos Sprague-Dawley , Soluções para Reidratação/farmacologia , Resultado do Tratamento
20.
Biomed Res Int ; 2019: 9845709, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984789

RESUMO

Aims: To investigate whether bone marrow derived mesenchymal stromal cells (BMSC) have ameliorated ischemia/reperfusion injury-induced acute kidney injury (IRI-AKI) via tumor necrosis factor-inducible gene 6 protein (TSG-6) and how TSG-6 exerted this effect. Methods: We used lentiviral vectors of short hairpin RNA (shRNA) targeting TSG-6 gene to silence TSG-6 in BMSC. And TSG-6-silenced BMSC were administrated into IRI-AKI rats. Then we analyzed serum creatinine (Scr) and renal histology of IRI-AKI rats treated with BMSC after different pretreatments. Furthermore, we explored the effect of TSG-6 on renal tubular epithelial cells proliferation in vivo and in vitro assays. Results: The Scr levels of IRI-AKI rats treated with BMSC (73.5±7.8 µmol/L) significantly decreased compared to those of IRI-AKI rats treated without BMSC (392.5±24.8 µmol/L, P<0.05) or with DMEM (314.0±19.8 µmol/L, P<0.05). Meanwhile, the renal tissue injury in IRI-AKI rats treated with BMSC improved markedly. However, the Scr levels of IRI-AKI rats treated with TSG-6-silenced BMSC (265.1±21.2 µmol/L) significantly increased compared to those with BMSC (74.0±8.5 µmol/L, P<0.05). The proportion of Ki67-positive cells was reduced in IRI-AKI rats treated with TSG-6-silenced BMSC compared to that in IRI-AKI rats treated with BMSC (29.7±0.8% versus 43.4±3.0%, P<0.05). In vitro, the cell proliferation rate of TSG-6-stimulated NRK-52E cells under hypoxia (89.2±3.9%) increased significantly compared to that of NRK-52E cells alone under hypoxia (82.4±0.8%, P<0.05). Similarly, the proportion of Ki67-positive cells was significantly elevated in TSG-6-stimulated NRK-52E cells under hypoxia. Furthermore, TSG-6 could inhibit infiltration of neutrophils in kidney tissue of IRI-AKI. Conclusions: TSG-6 plays a key role in the treatment of IRI-AKI with BMSC, which may be due to its effect on promoting renal tubular epithelial cells proliferation by modulating inflammation.


Assuntos
Lesão Renal Aguda/genética , Moléculas de Adesão Celular/genética , Transplante de Células-Tronco Mesenquimais , Traumatismo por Reperfusão/genética , Lesão Renal Aguda/patologia , Lesão Renal Aguda/terapia , Animais , Apoptose/genética , Células da Medula Óssea/citologia , Hipóxia Celular/genética , Linhagem Celular , Proliferação de Células/genética , Células Epiteliais/patologia , Humanos , Rim/lesões , Rim/metabolismo , Rim/patologia , Túbulos Renais/patologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Neutrófilos/patologia , Ratos , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia
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