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1.
Life Sci ; 257: 118004, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621918

RESUMO

BACKGROUND: Patients undergoing cardiopulmonary bypass (CPB) often develop acute kidney injury (AKI) caused by myocardial ischemia reperfusion (MI/R), and this renal injury can be resolved notably by dexmedetomidine. Endoplasmic reticulum (ER) stress was reported to get involved in organ injury including AKI. OBJECTIVES: The current study aimed to address the correlation between MI/R induced AKI with ER stress and to assess the effects of dexmedetomidine pretreatment on AKI protection. METHOD: Patients selected for heart valve replacement surgery were randomly assigned to NS group (pre-anesthesia with 0.9% NaCl) and DEX group (pre-anesthesia with dexmedetomidine). Rat MI/R model was induced by occluding coronary artery for 30 min followed by 48-hour reperfusion. Rats were randomized into Sham (0.9% NaCl), I/R (MI/R + 0.9% NaCl) and I/R + DEX (MI/R + dexmedetomidine). Organ function and ER stress condition were evaluated by blood chemistry, pathology, and molecular test. RESULTS: Clinical data indicated dexmedetomidine pretreatment attenuated AKI and oxidative stress as well as postischemic myocardial injury in patients. Accordingly animal results suggested dexmedetomidine reduced cellular injury and improved postischemic myocardial and renal function. Dexmedetomidine also reduced myocardial and renal cells apoptosis and down-regulated ER stress. CONCLUSIONS: These results suggested that dexmedetomidine pretreatment attenuates MI/R injury-induced AKI by relieving the ER stress.


Assuntos
Dexmedetomidina/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/prevenção & controle , Idoso , Animais , Apoptose/efeitos dos fármacos , China , Dexmedetomidina/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , Isquemia/metabolismo , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/metabolismo , Reperfusão Miocárdica/métodos , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estudos Prospectivos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
PLoS One ; 15(7): e0235849, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649695

RESUMO

Nephrotoxicity severely limits the chemotherapeutic efficacy of cisplatin (CDDP). Oxidative stress is associated with CDDP-induced acute kidney injury (AKI). Methylglyoxal (MG) forms advanced glycation end products that elevate oxidative stress. We aimed to explore the role of MG and its metabolite D-lactate and identify the proteins involved in CDDP-induced AKI. Six-week-old female BALB/c mice were intraperitoneally administered CDDP (5 mg/kg/day) for 3 or 5 days. Blood urea nitrogen (42.6 ± 7.4 vs. 18.3 ± 2.5; p < 0.05) and urinary N-acetyl-ß-D-glucosaminide (NAG; 4.89 ± 0.61 vs. 2.43 ± 0.31 U/L; p < 0.05) were significantly elevated in the CDDP 5-day group compared to control mice. Histological analysis confirmed AKI was successfully induced. Confocal microscopy revealed TNF-α was significantly increased in the CDDP 5-day group. Fluorogenic derivatized liquid chromatography-tandem mass spectrometry (FD-LC-MS/MS) showed the kidney MG (36.25 ± 1.68 vs. 18.95 ± 2.24 mg/g protein, p < 0.05) and D-lactate (1.78 ± 0.29 vs. 1.12 ± 0.06 mol/g protein, p < 0.05) contents were significantly higher in the CDDP 5-day group than control group. FD-LC-MS/MS proteomics identified 33 and nine altered peaks in the CDDP 3-day group and CDDP 5-day group (vs. control group); of the 35 proteins identified using the MOSCOT database, 11 were antioxidant-related. Western blotting confirmed that superoxide dismutase 1 (SOD-1) and parkinson disease protein 7 (DJ-1) are upregulated and may participate with MG in CDDP-induced AKI. This study demonstrates TNF-α, MG, SOD-1 and DJ-1 play crucial roles in CDDP-induced AKI.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Ácido Láctico/análise , Aldeído Pirúvico/análise , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Cromatografia Líquida , Feminino , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Ácido Láctico/metabolismo , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Aldeído Pirúvico/metabolismo , Espectrometria de Massas em Tandem
3.
Nat Commun ; 11(1): 3383, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636391

RESUMO

The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptive proliferation of tubular epithelial cells, but repair can also lead to fibrosis and progressive kidney disease. There is currently limited knowledge about transcriptional regulators regulating these repair programs. Herein we establish the enhancer and super-enhancer landscape after AKI by ChIP-seq in uninjured and repairing kidneys on day two after ischemia reperfusion injury (IRI). We identify key transcription factors including HNF4A, GR, STAT3 and STAT5, which show specific binding at enhancer and super-enhancer sites, revealing enhancer dynamics and transcriptional changes during kidney repair. Loss of bromodomain-containing protein 4 function before IRI leads to impaired recovery after AKI and increased mortality. Our comprehensive analysis of epigenetic changes after kidney injury in vivo has the potential to identify targets for therapeutic intervention. Importantly, our data also call attention to potential caveats involved in use of BET inhibitors in patients at risk for AKI.


Assuntos
Lesão Renal Aguda/genética , Elementos Facilitadores Genéticos , Túbulos Renais/citologia , Lesão Renal Aguda/metabolismo , Motivos de Aminoácidos , Animais , Sítios de Ligação , Proliferação de Células , Epigênese Genética , Fibrose , Fator 4 Nuclear de Hepatócito/metabolismo , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Nucleares , Receptores de Glucocorticoides/metabolismo , Elementos Reguladores de Transcrição , Traumatismo por Reperfusão/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Fatores de Transcrição , Transcrição Genética
4.
Life Sci ; 258: 118161, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730835

RESUMO

AIMS: Tubulointerstitial inflammation is recognized as a key determinant of progressive sepsis-induced acute kidney injury (AKI). Schisantherin A (SchA) has been shown to be capable of regulating inflammatory processes. In the present study, we explored the possibility of SchA in preventing lipopolysaccharide (LPS)-induced kidney inflammation and injury. MATERIALS AND METHODS: AKI was induced by a single intraperitoneal injection of LPS in CD1 mice, administration of SchA was used for treatment. The protective effect of SchA on renal function and inflammation were analyzed respectively; the NRK-52E cell line was employed for the in vitro study and relative molecular mechanism was explored. KEY FINDINGS: Administration with SchA markedly attenuated LPS-induced damage on renal function and histopathological changes of the kidney. Additionally, pretreatment with SchA could inhibit the expression of inflammatory factors in the kidneys. In NRK-52E cells, SchA treatment significantly inhibited LPS-induced NF-κB activation and pro-inflammatory cytokine expression. Moreover, SchA could promote NRF2 pathway activation, and further blockade of NRF2 activation reversed the SchA-induced inhibition of NF-κB activation. SIGNIFICANCE: These presented results indicated that SchA may have great potential for protecting against sepsis-induced AKI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Anti-Inflamatórios/uso terapêutico , Ciclo-Octanos/uso terapêutico , Dioxóis/uso terapêutico , Lignanas/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Sepse/complicações , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Ratos , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/patologia , Transdução de Sinais/efeitos dos fármacos
5.
Eur Urol Focus ; 6(5): 1086-1096, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32540268

RESUMO

CONTEXT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that erupted in December 2019 has affected more than a million people from over 200 countries, claiming over 70 000 lives (by April 7, 2020). As the viral infection is driven by increased angiotensin-converting enzyme-2 (ACE2) expression, with the kidney exhibiting the highest expression, it is crucial to gain insights into the mechanisms underlying renal cell carcinoma (RCC) and coronavirus disease 2019 (COVID-19). OBJECTIVE: This study considers up-to-date information on the biological determinants shared by COVID-19 and renal disease, and aims to provide evidence-based recommendations for the clinical management of RCC patients with COVID-19. EVIDENCE ACQUISITION: A literature search was performed using all sources (MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science). As of March 31, 2020, the Center for Disease Control reported that of the adults hospitalized for COVID-19 with underlying conditions in the USA, 74.8% had chronic renal disease. EVIDENCE SYNTHESIS: Evidence is discussed from epidemiological studies on SARS-CoV-2 pandemic and molecular studies on the role of kidney in facilitating routes for SARS-CoV-2 entry, leading to increased virulence of SARS-CoV-2 and clinical manifestation of symptoms in RCC. CONCLUSIONS: This analysis will advance our understanding of (1) the molecular signatures shared by RCC and COVID-19 and (2) the clinical implications of overlapping signaling pathways in the therapeutic management of RCC and COVID-19 patients. PATIENT SUMMARY: Amid the coronavirus disease 2019 (COVID-19) pandemic, patients diagnosed with renal cell carcinoma and infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may receive complimentary treatment modalities to enhance therapeutic response.


Assuntos
Betacoronavirus/metabolismo , Carcinoma de Células Renais/metabolismo , Infecções por Coronavirus/metabolismo , Neoplasias Renais/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Insuficiência Renal Crônica/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/terapia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antivirais/uso terapêutico , Carcinoma de Células Renais/epidemiologia , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hospitalização , Humanos , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/epidemiologia , Biópsia Líquida , Nivolumabe/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Inibidores de Proteínas Quinases/uso terapêutico , Diálise Renal , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Serina Endopeptidases/metabolismo , Índice de Gravidade de Doença , Sunitinibe/uso terapêutico
6.
Proc Natl Acad Sci U S A ; 117(27): 15874-15883, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571916

RESUMO

After acute kidney injury (AKI), patients either recover or alternatively develop fibrosis and chronic kidney disease. Interactions between injured epithelia, stroma, and inflammatory cells determine whether kidneys repair or undergo fibrosis, but the molecular events that drive these processes are poorly understood. Here, we use single nucleus RNA sequencing of a mouse model of AKI to characterize cell states during repair from acute injury. We identify a distinct proinflammatory and profibrotic proximal tubule cell state that fails to repair. Deconvolution of bulk RNA-seq datasets indicates that this failed-repair proximal tubule cell (FR-PTC) state can be detected in other models of kidney injury, increasing during aging in rat kidney and over time in human kidney allografts. We also describe dynamic intercellular communication networks and discern transcriptional pathways driving successful vs. failed repair. Our study provides a detailed description of cellular responses after injury and suggests that the FR-PTC state may represent a therapeutic target to improve repair.


Assuntos
Lesão Renal Aguda/metabolismo , Túbulos Renais Proximais/metabolismo , Rim/metabolismo , Transcriptoma , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Aloenxertos , Animais , Modelos Animais de Doenças , Fibrose , Redes Reguladoras de Genes , Humanos , Rim/lesões , Túbulos Renais Proximais/lesões , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Análise de Sequência de RNA , Células Estromais/metabolismo , Células Estromais/patologia
7.
Anaesth Crit Care Pain Med ; 39(4): 453-455, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32565254

RESUMO

The pathophysiology of acute kidney injury (AKI) in COVID-19 patients is still poorly understood. SARS-CoV-2 has been suggested to modulate the renin-angiotensin-aldosterone system (RAAS). In this series of COVID-19 critically ill patients, we report evidence of activation of the RAAS in COVID-19 patients with AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Betacoronavirus , Infecções por Coronavirus/metabolismo , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina/fisiologia , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/terapia , Idoso , Aldosterona/sangue , Infecções por Coronavirus/complicações , Creatinina/sangue , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações
8.
Am J Physiol Renal Physiol ; 319(2): F229-F244, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32538150

RESUMO

Sepsis-associated acute kidney injury (s-AKI) has a staggering impact in patients and lacks any treatment. Incomplete understanding of the pathogenesis of s-AKI is a major barrier to the development of effective therapies. We address the gaps in knowledge regarding renal oxygenation, tubular metabolism, and mitochondrial function in the pathogenesis of s-AKI using the cecal ligation and puncture (CLP) model in mice. At 24 h after CLP, renal oxygen delivery was reduced; however, fractional oxygen extraction was unchanged, suggesting inefficient renal oxygen utilization despite decreased glomerular filtration rate and filtered load. To investigate the underlying mechanisms, we examined temporal changes in mitochondrial function and metabolism at 4 and 24 h after CLP. At 4 h after CLP, markers of mitochondrial content and biogenesis were increased in CLP kidneys, but mitochondrial oxygen consumption rates were suppressed in proximal tubules. Interestingly, at 24 h, proximal tubular mitochondria displayed high respiratory capacity, but with decreased mitochondrial content, biogenesis, fusion, and ATP levels in CLP kidneys, suggesting decreased ATP synthesis efficiency. We further investigated metabolic reprogramming after CLP and observed reduced expression of fatty acid oxidation enzymes but increased expression of glycolytic enzymes at 24 h. However, assessment of functional glycolysis revealed lower glycolytic capacity, glycolytic reserve, and compensatory glycolysis in CLP proximal tubules, which may explain their susceptibility to injury. In conclusion, we demonstrated significant alterations in renal oxygenation, tubular mitochondrial function, and metabolic reprogramming in s-AKI, which may play an important role in the progression of injury and recovery from AKI in sepsis.


Assuntos
Lesão Renal Aguda/patologia , Rim/lesões , Mitocôndrias/metabolismo , Sepse/complicações , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/metabolismo , Animais , Modelos Animais de Doenças , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Camundongos Endogâmicos C57BL , Sepse/metabolismo
9.
Am J Physiol Renal Physiol ; 319(2): F245-F255, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32567348

RESUMO

Ca2+ is an important second messenger that translates extracellular stimuli into intracellular responses. Although there has been significant progress in understanding Ca2+ dynamics in organs such as the brain, the nature of Ca2+ signals in the kidney is still poorly understood. Here, we show that by using a genetically expressed highly sensitive reporter (GCaMP6s), it is possible to perform imaging of Ca2+ signals at high resolution in the mouse kidney in vivo. Moreover, by applying machine learning-based automated analysis using a Ca2+-independent signal, quantitative data can be extracted in an unbiased manner. By projecting the resulting data onto the structure of the kidney, we show that different tubular segments display highly distinct spatiotemporal patterns of Ca2+ signals. Furthermore, we provide evidence that Ca2+ activity in the proximal tubule decreases with increasing distance from the glomerulus. Finally, we demonstrate that substantial changes in intracellular Ca2+ can be detected in proximal tubules in a cisplatin model of acute kidney injury, which can be linked to alterations in cell structure and transport function. In summary, we describe a powerful new tool to investigate how single cell behavior is integrated with whole organ structure and function and how it is altered in disease states relevant to humans.


Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Glomérulos Renais/metabolismo , Túbulos Renais Proximais/metabolismo , Lesão Renal Aguda/metabolismo , Animais , Humanos , Rim/anatomia & histologia , Rim/metabolismo , Túbulos Renais Proximais/anatomia & histologia , Camundongos
10.
Life Sci ; 254: 117791, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32416166

RESUMO

AIMS: Sepsis-induced acute kidney injury (SI-AKI) is the fifth most common cause of hospital-acquired acute kidney injury. Pannexin1 (Panx1) triggers inflammation and apoptosis which act as crucial factors in the pathogenesis of SI-AKI. We aimed to investigate the expression of Panx1 and its role on the inflammation and apoptosis in SI-AKI. MATERIALS AND METHODS: SI-AKI model was established by lipopolysaccharide (LPS) injection in mice and LPS-treated HK-2 cells in vitro. Panx1 was inhibited by pretreating with carbenoxolone (CBX) or small interfering RNA in vivo and vitro, respectively. The expression of Panx1 was determined by qPCR, western blot and immunohistochemistry (IHC). Kidney damage was evaluated by kidney function, histopathological examination and AKI biomarkers. Inflammatory cytokines were detected by qPCR and ELISA. Apoptosis was detected by TUNEL staining and the expression of apoptosis-related proteins. The activation of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome was measured by western blot. KEY FINDINGS: Panx1 increased in LPS-induced SI-AKI mice and HK-2 cells, as well as in SI-AKI patients. CBX alleviated the renal function and pathological damage, as well as decreased the mRNA of kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Inhibiting Panx1 decreased the production of IL-1ß, IL-6 and TNF-α, as well as tubular cell apoptosis in SI-AKI. Inhibiting Panx1 suppressed inflammatory cytokines and apoptosis via inhibiting NLRP3 inflammasome activation and regulating apoptotic protein Bax and Bcl2 expression, respectively. SIGNIFICANCE: These observations suggest that pharmacological inhibition of Panx1 might be a potential approach in the clinical therapy of SI-AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Apoptose/efeitos dos fármacos , Carbenoxolona/farmacologia , Conexinas/antagonistas & inibidores , Citocinas/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Lesão Renal Aguda/complicações , Lesão Renal Aguda/patologia , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Biomarcadores/metabolismo , Conexinas/biossíntese , Humanos , Inflamassomos/metabolismo , Inflamação/complicações , Inflamação/prevenção & controle , Rim/metabolismo , Rim/patologia , Testes de Função Renal , Lipopolissacarídeos , Masculino , Camundongos , Proteínas do Tecido Nervoso/biossíntese , RNA Interferente Pequeno/farmacologia , Sepse/complicações
11.
Gene ; 753: 144789, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32442578

RESUMO

BACKGROUND: This study determined the possible anti-inflammatory and antioxidant renal protective effect of genistein, a soy isoflavone, against kidney damage and functional disorders following renal ischemia/reperfusion (I/R) in male rats. MATERIALS AND METHODS: The animals were dedicated to five groups (n = 7 per group): Sham, Sham + Geni (genistein, 15 mg/kg in 1 ml 1% DMSO, i.p.), Sham + DMSO (1 ml 1% DMSO, i.p.), I/R (bilateral renal ischemia for 45 min followed by 24 h reperfusion), I/R + Geni (genistein, 15 mg/kg). 24-h urine samples, blood and tissue samples of the kidney were collected at the end of 24 h reperfusion period. RESULTS: Compared to sham, sham + Geni and sham + DMSO groups, IR injury (IRI) ended in kidney dysfunction (decreased creatinine clearance, and increased fractional excretion of sodium), increased levels of malondialdehyde, decreased activities of antioxidant enzymes (superoxide dismutase, gluthatione peroxidase, and catalase), increased gene expression levels of TLR4 (Toll-like receptor 4) and TNF-α (tumor necrosis factor-alpha), as well as histological damages in kidney tissue. Genistein administration decreased all the changes. Therefore, genistein apparently protects the kidney against IRI by mitigating both oxidative stress and inflammation. The antioxidant and anti-inflammatory properties of genistein probably exert important roles in improving functional disorders and offer renal protection against IRI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Genisteína/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/metabolismo , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Genisteína/metabolismo , Inflamação/metabolismo , Isquemia/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
Cell Prolif ; 53(6): e12829, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32419317

RESUMO

OBJECTIVE: Acute kidney injury (AKI) is a common complication of acute liver failure (ALF). Pyroptosis is a necrosis type related to inflammation. This study aimed to investigate the role of TNF-α/HMGB1 pathway in pyroptosis during ALF and AKI. METHODS: An ALF and AKI mouse model was generated using LPS/D-Gal, and a TNF-α inhibitor, CC-5013, was used to treat the mice. THP-1 cells were induced to differentiate into M1 macrophages, then challenged with either CC-5013 or an HMGB1 inhibitor, glycyrrhizin. pLVX-mCMVZsGreen-PGK-Puros plasmids containing TNF-α wild-type (WT), mutation A94T of TNF-α and mutation P84L of TNF-α were transfected into M1 macrophages. RESULTS: Treatment with CC-5013 decreased the activation of TNF-α/HMGB1 pathway and pyroptosis in the treated mice and cells compared with the control mice and cells. CC-5013 also ameliorated liver and kidney pathological changes and improved liver and renal functions in treated mice, and the number of M1 macrophages in the liver and kidney tissues also decreased. The activation of TNF-α/HMGB1 pathway and pyroptosis increased in the M1 macrophage group compared with the normal group. Similarly, the activation of TNF-α/HMGB1 pathway and pyroptosis in the LPS + WT group also increased. By contrast, the activation of the TNF-α/HMGB1 pathway and pyroptosis decreased in the LPS + A94T and LPS + P84L groups. Moreover, glycyrrhizin inhibited pyroptosis. CONCLUSION: The TNF-α/HMGB1 inflammation signalling pathway plays an important role in pyroptosis during ALF and AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Proteína HMGB1/fisiologia , Falência Hepática Aguda/metabolismo , Piroptose , Fator de Necrose Tumoral alfa/fisiologia , Lesão Renal Aguda/sangue , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Ácido Glicirrízico/farmacologia , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Humanos , Inflamação/metabolismo , Lenalidomida/farmacologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética
13.
Am J Kidney Dis ; 76(1): 144-147, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32387022

RESUMO

We report a case of a patient who developed dialysis-requiring acute kidney injury (AKI) after the use of canagliflozin. A 66-year-old man with type 2 diabetes who was recovering from left knee septic arthritis at a rehabilitation facility was admitted with oliguric AKI 5 days after starting treatment with canagliflozin, an inhibitor of sodium/glucose cotransporter 2 (SGLT2). The patient presented with hematuria, non-nephrotic-range proteinuria, and serum creatinine level of 6.8 (baseline, 1.1-1.3) mg/dL. There was no recent use of radiocontrast agents or exposure to other nephrotoxins. The patient subsequently required hemodialysis. Due to recent antibiotic use (ampicillin-sulbactam), acute interstitial nephritis was considered in the differential diagnosis. Kidney biopsy was performed, which showed the presence of osmotic nephropathy. The patient's kidney function returned to baseline after 2 weeks of hemodialysis. This case provides evidence of an association of osmotic nephropathy with the use of canagliflozin and discusses potential mechanisms. We recommend kidney biopsy for cases of severe AKI associated with SGLT2 inhibitors to better understand the relationship of this complication with the use of this class of medications.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/diagnóstico por imagem , Canagliflozina/efeitos adversos , Nefrose/induzido quimicamente , Nefrose/diagnóstico por imagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Lesão Renal Aguda/metabolismo , Idoso , Diuréticos Osmóticos/efeitos adversos , Humanos , Masculino , Nefrose/metabolismo
18.
Nat Commun ; 11(1): 1924, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317630

RESUMO

Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Células Epiteliais/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição SOX9/metabolismo , Animais , Morte Celular , Células Epiteliais/metabolismo , Feminino , Proteínas de Fluorescência Verde/metabolismo , Humanos , Queratinócitos/metabolismo , Rim/metabolismo , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo
19.
PLoS One ; 15(4): e0230934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240220

RESUMO

BACKGROUND: There are still limited studies comprehensively examining the diagnostic performance of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C in contrast-induced nephropathy (CIN). The study aimed to investigate and compare the predictive value of NGAL and cystatin C in the early diagnosis of CIN. METHODS AND MATERIALS: We searched the PubMed, EMBASE and Cochrane Library databases until November 10, 2019. The methodological quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Bivariate modeling and hierarchical summary receiver operating characteristic (HSROC) modeling were performed to summarize and compare the diagnostic performance of blood/urine NGAL and serum cystatin C in CIN. Subgroup and meta-regression analyses were performed according to the study and patient characteristics. RESULTS: Thirty-seven studies from thirty-one original studies were included (blood NGAL, 1840 patients in 9 studies; urine NGAL, 1701 patients in 10 studies; serum cystatin C, 5509 patients in 18 studies). Overall, serum cystatin C performed better than serum/urine NGAL (pooled DOR: 43 (95%CI: 12-152); AUROC: 0.93; λ: 3.79); serum and urine NGAL had a similar diagnostic performance (pooled DOR: 25 (95%CI: 6-108)/22(95%CI: 8-64); AUROC: 0.90/0.89; λ: 3.20/3.08). Meta-regression analysis indicated that the sources of heterogeneity might be CIN definition, assays, and nationalities. CONCLUSION: Both NGAL and cystatin C can serve as early diagnostic indicators of CIN, while cystatin C may perform better than NGAL.


Assuntos
Lesão Renal Aguda/sangue , Lesão Renal Aguda/diagnóstico , Cistatina C/sangue , Gelatinases/sangue , Lipocalinas/sangue , Neutrófilos/metabolismo , Lesão Renal Aguda/metabolismo , Animais , Humanos
20.
Am J Physiol Renal Physiol ; 318(4): F971-F978, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150447

RESUMO

Acute kidney injury (AKI) remains a major global healthcare problem, and there is a need to develop human-based models to study AKI in vitro. Toward this goal, we have characterized induced pluripotent stem cell-derived human kidney organoids and their response to cisplatin, a chemotherapeutic drug that induces AKI and preferentially damages the proximal tubule. We found that a single treatment with 50 µM cisplatin induces hepatitis A virus cellular receptor 1 (HAVCR1) and C-X-C motif chemokine ligand 8 (CXCL8) expression, DNA damage (γH2AX), and cell death in the organoids but greatly impairs organoid viability. DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial cell populations. This lack of specificity correlated with low expression of proximal tubule-specific SLC22A2/organic cation transporter 2 (OCT2) for cisplatin. To improve viability, we developed a repeated low-dose regimen of 4 × 5 µM cisplatin over 7 days and found this caused less toxicity while still inducing a robust injury response that included secretion of known AKI biomarkers and inflammatory cytokines. This work validates the use of human kidney organoids to model aspects of cisplatin-induced injury, with the potential to identify new AKI biomarkers and develop better therapies.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Dano ao DNA , Túbulos Renais Proximais/efeitos dos fármacos , Organoides/efeitos dos fármacos , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Antineoplásicos/metabolismo , Células Cultivadas , Cisplatino/metabolismo , Relação Dose-Resposta a Droga , Receptor Celular 1 do Vírus da Hepatite A/genética , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Histonas/metabolismo , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Transportador 2 de Cátion Orgânico/metabolismo , Organoides/metabolismo , Organoides/patologia , Fatores de Tempo
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