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1.
Biomed Pharmacother ; 169: 115925, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38007933

RESUMO

BACKGROUND: Rhabdomyolysis is a severe clinical syndrome associated to acute kidney injury (AKI) and chronic kidney disease (CKD). TWEAK/Fn14 signaling axis regulates renal inflammation and tubular cell death. However, the functional role of TWEAK/Fn14 in rhabdomyolysis remains unknown. METHODS: Rhabdomyolysis was induced in wild-type, TWEAK- and Fn14-deficient mice or mice treated with TWEAK blocking antibody. Renal injury, inflammation, fibrosis and cell death were assessed. Additionally, we performed in vivo and in vitro studies to explore the possible signalling pathways involved in Fn14 regulation. FINDINGS: Fn14 renal expression was increased in mice with rhabdomyolysis, correlating with decline of renal function. Mechanistically, myoglobin (Mb) induced Fn14 expression via ERK and p38 pathway, whereas Nrf2 activation diminished Mb-mediated Fn14 upregulation in cultured renal cells. TWEAK or Fn14 genetic depletion ameliorated rhabdomyolysis-associated loss of renal function, histological damage, tubular cell death, inflammation, and expression of both tubular and endothelial injury markers. Deficiency of TWEAK or Fn14 also decreased long-term renal inflammation and fibrosis in mice with rhabdomyolysis. Finally, pharmacological treatment with a blocking TWEAK antibody diminished the expression of acute renal injury markers and cell death and lessened residual kidney fibrosis and chronic inflammation in rhabdomyolysis. INTERPRETATION: TWEAK/Fn14 axis participates in the pathogenesis of rhabdomyolysis-AKI and subsequent AKI-CKD transition. Blockade of this signaling pathway may represent a promising therapeutic strategy for reducing rhabdomyolysis-mediated renal injury. FUNDING: Spanish Ministry of Science and Innovation, ISCIII and Junta de Andalucía.


Assuntos
Injúria Renal Aguda , Insuficiência Renal Crônica , Rabdomiólise , Animais , Camundongos , Injúria Renal Aguda/metabolismo , Citocina TWEAK/metabolismo , Fibrose , Inflamação , Rabdomiólise/complicações , Fatores de Necrose Tumoral/metabolismo , Receptor de TWEAK/metabolismo
2.
Cell Signal ; 104: 110583, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36596353

RESUMO

Chronic kidney disease (CKD) is a global health condition characterized by a progressive deterioration of kidney function. It is associated with high serum levels of uremic toxins (UT), such as Indoxyl Sulfate (IS), which may participate in the genesis of several uremic complications. Anemia is one of the major complications in CKD patients that contribute to cardiovascular disease, increase morbi-mortality, and is associated with a deterioration of kidney failure in these patients. Our study aimed to characterize the impact of IS on CKD-related erythropoiesis. Using cellular and pre-clinical models, we studied cellular and molecular effects of IS on the growth and differentiation of erythroid cells. First, we examined the effect of clinically relevant concentrations of IS (up to 250 µM) in the UT7/EPO cell line. IS at 250 µM increased apoptosis of UT7/EPO cells at 48 h compared to the control condition. We confirmed this apoptotic effect of IS in erythropoiesis in human primary CD34+ cells during the later stages of erythropoiesis. Then, in IS-treated human primary CD34+ cells and in a (5/6 Nx) mice model, a blockage at the burst-forming unit-erythroid (BFU-E) stage of erythropoiesis was also observed. Finally, IS deregulates a number of erythropoietic related genes such as GATA-1, Erythropoietin-Receptor (EPO-R), and ß-globin. Our findings suggest that IS could affect cell viability and differentiation of erythroid progenitors by altering erythropoiesis and contributing to the development of anemia in CKD.


Assuntos
Anemia , Eritropoetina , Insuficiência Renal Crônica , Camundongos , Animais , Humanos , Eritropoese/fisiologia , Indicã/metabolismo , Indicã/farmacologia , Células Precursoras Eritroides/metabolismo , Anemia/metabolismo , Insuficiência Renal Crônica/metabolismo
3.
J Pathol ; 258(3): 236-249, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35903022

RESUMO

Massive intravascular hemolysis is a common characteristic of several pathologies. It is associated with the release of large quantities of heme into the circulation, promoting injury in vulnerable organs, mainly kidney, liver, and spleen. Heme activates Toll-like receptor 4 (TLR4), a key regulator of the inflammatory response; however, the role of TLR4 in hemolysis and whether inhibition of this receptor may protect from heme-mediated injury are unknown. We induced intravascular hemolysis by injection of phenylhydrazine in wildtype and Tlr4-knockout mice. In this model, we analyzed physiological parameters, histological damage, inflammation and cell death in kidney, liver, and spleen. We also evaluated whether heme-mediated-inflammatory effects were prevented by TLR4 inhibition with the compound TAK-242, both in vivo and in vitro. Induction of massive hemolysis elicited acute kidney injury characterized by loss of renal function, morphological alterations of the tubular epithelium, cell death, and inflammation. These pathological effects were significantly ameliorated in the TLR4-deficient mice and in wildtype mice treated with TAK-242. In vitro studies showed that TAK-242 pretreatment reduced heme-mediated inflammation by inhibiting the TLR4/NF-κB (nuclear factor kappa B) axis. However, analysis in liver and spleen indicated that TLR4 deficiency did not protect against the toxic accumulation of heme in these organs. In conclusion, TLR4 is a key molecule involved in the renal inflammatory response triggered by massive intravascular hemolysis. TLR4 inhibition may be a potential therapeutic approach to prevent renal damage in patients suffering from hemolysis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Hemólise , Receptor 4 Toll-Like , Animais , Modelos Animais de Doenças , Heme/metabolismo , Inflamação , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Fenil-Hidrazinas/farmacologia , Sulfonamidas , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
4.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199920

RESUMO

Recent progress in genomic research has highlighted the genome to be much more transcribed than expected. The formerly so-called junk DNA encodes a miscellaneous group of largely unknown RNA transcripts, which contain the long non-coding RNAs (lncRNAs) family. lncRNAs are instrumental in gene regulation. Moreover, understanding their biological roles in the physiopathology of many diseases, including renal, is a new challenge. lncRNAs regulate the effects of microRNAs (miRNA) on mRNA expression. Understanding the complex crosstalk between lncRNA-miRNA-mRNA is one of the main challenges of modern molecular biology. This review aims to summarize the role of lncRNA on kidney diseases, the molecular mechanisms involved, and their function as emerging prognostic biomarkers for both acute and chronic kidney diseases. Finally, we will also outline new therapeutic opportunities to diminish renal injury by targeting lncRNA with antisense oligonucleotides.


Assuntos
Regulação da Expressão Gênica , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo , Insuficiência Renal Crônica/patologia , Animais , Humanos , RNA Mensageiro/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo
5.
Clin Kidney J ; 14(1): 424-428, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33564448

RESUMO

The AngioJet technique combines localized thrombolysis and percutaneous mechanical thrombectomy (PMT). However, PMT may cause acute kidney injury (AKI), which has been ascribed to severe mechanical haemolysis, although no renal biopsies have been reported. We now report the first renal biopsy in a patient with AKI following PMT. There is histological evidence of haemoglobin (Hb)-induced tubular injury and podocyte stress characterized by intracellular Hb and staining for ferritin and hemo-oxygenase-1, suggestive of an adaptive response to oxidative stress. This confirms that Hb is involved in kidney cell injury and supports the existence of several different kidney cellular targets.

6.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467524

RESUMO

Acute kidney injury (AKI) is an important health problem, affecting 13.3 million individuals/year. It is associated with increased mortality, mainly in low- and middle-income countries, where renal replacement therapy is limited. Moreover, survivors show adverse long-term outcomes, including increased risk of developing recurrent AKI bouts, cardiovascular events, and chronic kidney disease. However, there are no specific treatments to decrease the adverse consequences of AKI. Epidemiological and preclinical studies show the pathological role of inflammation in AKI, not only at the acute phase but also in the progression to chronic kidney disease. Toll-like receptors (TLRs) are key regulators of the inflammatory response and have been associated to many cellular processes activated during AKI. For that reason, a number of anti-inflammatory agents targeting TLRs have been analyzed in preclinical studies to decrease renal damage during AKI. In this review, we updated recent knowledge about the role of TLRs, mainly TLR4, in the initiation and development of AKI as well as novel compounds targeting these molecules to diminish kidney injury associated to this pathological condition.


Assuntos
Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/terapia , Terapia de Substituição Renal/métodos , Receptores Toll-Like/metabolismo , Animais , Progressão da Doença , Humanos , Rim/metabolismo , Rim/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia , Fatores de Risco , Receptor 4 Toll-Like/metabolismo
7.
Nefrología (Madrid) ; 40(4): 384-394, jul.-ago. 2020. tab, ilus, graf
Artigo em Inglês | IBECS | ID: ibc-201936

RESUMO

Cell death is a finely regulated process occurring through different pathways. Regulated cell death, either through apoptosis or regulated necrosis offers the possibility of therapeutic intervention. Necroptosis and ferroptosis are among the best studied forms of regulated necrosis in the context of kidney disease. We now review the current evidence supporting a role for ferroptosis in kidney disease and the implications of this knowledge for the design of novel therapeutic strategies. Ferroptosis is defined functionally, as a cell modality characterized by peroxidation of certain lipids, constitutively suppressed by GPX4 and inhibited by iron chelators and lipophilic antioxidants. There is functional evidence of the involvement of ferroptosis in diverse forms of kidneys disease. In a well characterized nephrotoxic acute kidney injury model, ferroptosis caused an initial wave of death, triggering an inflammatory response that in turn promoted necroptotic cell death that perpetuated kidney dysfunction. This suggests that ferroptosis inhibitors may be explored as prophylactic agents in clinical nephrotoxicity or ischemia-reperfusion injury such as during kidney transplantation. Transplantation offers the unique opportunity of using anti-ferroptosis agent ex vivo, thus avoiding bioavailability and in vivo pharmacokinetics and pharmacodynamics issues


La muerte celular es un proceso minuciosamente regulado que se desarrolla a través de diferentes vías. La muerte celular regulada, ya sea mediante apoptosis o necrosis regulada, ofrece la posibilidad de introducir una intervención terapéutica. La necroptosis y la ferroptosis se encuentran entre las formas mejor estudiadas de necrosis regulada en el contexto de la nefropatía. Revisamos los datos actuales que avalan que la ferroptosis desempeña una función en la nefropatía y las repercusiones que tiene este conocimiento en el diseño de nuevas estrategias terapéuticas. La ferroptosis se define de forma funcional como una modalidad celular caracterizada por la peroxidación de ciertos lípidos, constitutivamente suprimida por GPX4 e inhibida por quelantes férricos y antioxidantes lipofílicos. Existen datos probatorios funcionales de la implicación de la ferroptosis en diversas formas de nefropatía. En un modelo de lesión renal aguda nefrotóxica bien caracterizado, la ferroptosis provocó una ola inicial de muerte, la cual desencadenó una respuesta inflamatoria que a su vez promovió la muerte celular necroptótica que perpetuó la disfunción renal. Esto sugiere que los inhibidores de la ferroptosis pueden explorarse como agentes profilácticos en la nefrotoxicidad clínica o en la lesión por isquemia-reperfusión, como durante un trasplante de riñón. Los trasplantes ofrecen una oportunidad única para el uso de agentes inhibidores de la ferroptosis ex vivo, con lo que se evitarían los problemas de biodisponibilidad y los problemas de farmacocinética y farmacodinámica in vivo


Assuntos
Humanos , Nefropatias/fisiopatologia , Morte Celular/genética , Morte Celular/fisiologia , Biomarcadores
8.
Nefrologia (Engl Ed) ; 40(4): 384-394, 2020.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32624210

RESUMO

Cell death is a finely regulated process occurring through different pathways. Regulated cell death, either through apoptosis or regulated necrosis offers the possibility of therapeutic intervention. Necroptosis and ferroptosis are among the best studied forms of regulated necrosis in the context of kidney disease. We now review the current evidence supporting a role for ferroptosis in kidney disease and the implications of this knowledge for the design of novel therapeutic strategies. Ferroptosis is defined functionally, as a cell modality characterized by peroxidation of certain lipids, constitutively suppressed by GPX4 and inhibited by iron chelators and lipophilic antioxidants. There is functional evidence of the involvement of ferroptosis in diverse forms of kidneys disease. In a well characterized nephrotoxic acute kidney injury model, ferroptosis caused an initial wave of death, triggering an inflammatory response that in turn promoted necroptotic cell death that perpetuated kidney dysfunction. This suggests that ferroptosis inhibitors may be explored as prophylactic agents in clinical nephrotoxicity or ischemia-reperfusion injury such as during kidney transplantation. Transplantation offers the unique opportunity of using anti-ferroptosis agent ex vivo, thus avoiding bioavailability and in vivo pharmacokinetics and pharmacodynamics issues.


Assuntos
Ferroptose , Nefropatias/etiologia , Ferroptose/fisiologia , Humanos , Nefropatias/terapia
9.
Int J Mol Sci ; 21(11)2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32471207

RESUMO

Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.


Assuntos
Anti-Inflamatórios/uso terapêutico , Nefropatias Diabéticas/metabolismo , Hipoglicemiantes/uso terapêutico , Imunossupressores/uso terapêutico , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/imunologia , Humanos
10.
Antioxidants (Basel) ; 10(1)2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33396350

RESUMO

Chronic kidney disease (CKD) is one of the fastest-growing causes of death and is predicted to become by 2040 the fifth global cause of death. CKD is characterized by increased oxidative stress and chronic inflammation. However, therapies to slow or prevent CKD progression remain an unmet need. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that plays a key role in protection against oxidative stress and regulation of the inflammatory response. Consequently, the use of compounds targeting Nrf2 has generated growing interest for nephrologists. Pre-clinical and clinical studies have demonstrated that Nrf2-inducing strategies prevent CKD progression and protect from acute kidney injury (AKI). In this article, we review current knowledge on the protective mechanisms mediated by Nrf2 against kidney injury, novel therapeutic strategies to induce Nrf2 activation, and the status of ongoing clinical trials targeting Nrf2 in renal diseases.

11.
Front Pharmacol ; 10: 740, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31333462

RESUMO

Massive intravascular hemolysis is associated with acute kidney injury (AKI). Nuclear factor erythroid-2-related factor 2 (Nrf2) plays a central role in the defense against oxidative stress by activating the expression of antioxidant proteins. We investigated the role of Nrf2 in intravascular hemolysis and whether Nrf2 activation protected against hemoglobin (Hb)/heme-mediated renal damage in vivo and in vitro. We observed renal Nrf2 activation in human hemolysis and in an experimental model of intravascular hemolysis promoted by phenylhydrazine intraperitoneal injection. In wild-type mice, Hb/heme released from intravascular hemolysis promoted AKI, resulting in decreased renal function, enhanced expression of tubular injury markers (KIM-1 and NGAL), oxidative and endoplasmic reticulum stress (ER), and cell death. These features were more severe in Nrf2-deficient mice, which showed decreased expression of Nrf2-related antioxidant enzymes, including heme oxygenase 1 (HO-1) and ferritin. Nrf2 activation with sulforaphane protected against Hb toxicity in mice and cultured tubular epithelial cells, ameliorating renal function and kidney injury and reducing cell stress and death. Nrf2 genotype or sulforaphane treatment did not influence the severity of hemolysis. In conclusion, our study identifies Nrf2 as a key molecule involved in protection against renal damage associated with hemolysis and opens novel therapeutic approaches to prevent renal damage in patients with severe hemolytic crisis. These findings provide new insights into novel aspects of Hb-mediated renal toxicity and may have important therapeutic implications for intravascular hemolysis-related diseases.

12.
Br J Pharmacol ; 176(15): 2764-2779, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31074003

RESUMO

BACKGROUND AND PURPOSE: Ischaemic stroke is a leading cause of death, disability, and a high unmet medical need. Post-reperfusion inflammation and an up-regulation of toll-like receptor 4 (TLR4), an upstream sensor of innate immunity, are associated with poor outcome in stroke patients. Here, we identified the therapeutic effect of targeting the LPS/TLR4 signal transduction pathway. EXPERIMENTAL APPROACH: We tested the effect of the TLR4 inhibitor, eritoran (E5564) in different in vitro ischaemia-related models: human organotypic cortex culture, rat organotypic hippocampal cultures, and primary mixed glia cultures. We explored the therapeutic window of E5564 in the transient middle cerebral artery occlusion model of cerebral ischaemia in mice. KEY RESULTS: In vivo, administration of E5564 1 and 4 hr post-ischaemia reduced the expression of different pro-inflammatory chemokines and cytokines, infarct volume, blood-brain barrier breakdown, and improved neuromotor function, an important clinically relevant outcome. In the human organotypic cortex culture, E5564 reduced the activation of microglia and ROS production evoked by LPS. CONCLUSION AND IMPLICATIONS: TLR4 signalling has a causal role in the inflammation associated with a poor post-stroke outcome. Importantly, its inhibition by eritoran (E5564) provides neuroprotection both in vitro and in vivo, including in human tissue, suggesting a promising new therapeutic approach for ischaemic stroke.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Lipídeo A/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Lipídeo A/farmacologia , Lipídeo A/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fenótipo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo
13.
Int J Mol Sci ; 20(9)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060307

RESUMO

Glomerular hematuria is a cardinal symptom of renal disease. Glomerular hematuria may be classified as microhematuria or macrohematuria according to the number of red blood cells in urine. Recent evidence suggests a pathological role of persistent glomerular microhematuria in the progression of renal disease. Moreover, gross hematuria, or macrohematuria, promotes acute kidney injury (AKI), with subsequent impairment of renal function in a high proportion of patients. In this pathological context, hemoglobin, heme, or iron released from red blood cells in the urinary space may cause direct tubular cell injury, oxidative stress, pro-inflammatory cytokine production, and further monocyte/macrophage recruitment. The aim of this manuscript is to review the role of glomerular hematuria in kidney injury, the role of inflammation as cause and consequence of glomerular hematuria, and to discuss novel therapies to combat hematuria.


Assuntos
Glomerulonefrite/complicações , Glomerulonefrite/fisiopatologia , Hematúria/etiologia , Hematúria/urina , Glomérulos Renais/fisiopatologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , Animais , Biomarcadores , Glomerulonefrite/diagnóstico , Glomerulonefrite/etiologia , Hematúria/diagnóstico , Humanos , Rim/patologia , Rim/fisiopatologia , Estresse Oxidativo , Fenótipo , Prognóstico
14.
FASEB J ; 33(8): 8961-8975, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31034781

RESUMO

Acute kidney injury is a common complication of rhabdomyolysis. A better understanding of this syndrome may be useful to identify novel therapeutic targets because there is no specific treatment so far. Ferroptosis is an iron-dependent form of regulated nonapoptotic cell death that is involved in renal injury. In this study, we investigated whether ferroptosis is associated with rhabdomyolysis-mediated renal damage, and we studied the therapeutic effect of curcumin, a powerful antioxidant with renoprotective properties. Induction of rhabdomyolysis in mice increased serum creatinine levels, endothelial damage, inflammatory chemokines, and cytokine expression, alteration of redox balance (increased lipid peroxidation and decreased antioxidant defenses), and tubular cell death. Treatment with curcumin initiated before or after rhabdomyolysis induction ameliorated all these pathologic and molecular alterations. Although apoptosis or receptor-interacting protein kinase (RIPK)3-mediated necroptosis were activated in rhabdomyolysis, our results suggest a key role of ferroptosis. Thus, treatment with ferrostatin 1, a ferroptosis inhibitor, improved renal function in glycerol-injected mice, whereas no beneficial effects were observed with the pan-caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-(O-methyl)-fluoromethylketone or in RIPK3-deficient mice. In cultured renal tubular cells, myoglobin (Mb) induced ferroptosis-sensitive cell death that was also inhibited by curcumin. Mechanistic in vitro studies showed that curcumin reduced Mb-mediated inflammation and oxidative stress by inhibiting the TLR4/NF-κB axis and activating the cytoprotective enzyme heme oxygenase 1. Our findings are the first to demonstrate the involvement of ferroptosis in rhabdomyolysis-associated renal damage and its sensitivity to curcumin treatment. Therefore, curcumin may be a potential therapeutic approach for patients with this syndrome.-Guerrero-Hue, M., García-Caballero, C., Palomino-Antolín, A., Rubio-Navarro, A., Vázquez-Carballo, C., Herencia, C., Martín-Sanchez, D., Farré-Alins, V., Egea, J., Cannata, P., Praga, M., Ortiz, A., Egido, J., Sanz, A. B., Moreno, J. A. Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis-mediated cell death.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Curcumina/farmacologia , Ferroptose/efeitos dos fármacos , Rabdomiólise/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Antioxidantes/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mioglobina/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Rabdomiólise/complicações , Rabdomiólise/patologia , Receptor 4 Toll-Like/metabolismo
15.
Nefrología (Madrid) ; 38(1): 13-26, ene.-feb. 2018. ilus, graf, tab
Artigo em Espanhol | IBECS | ID: ibc-170077

RESUMO

La hemoglobina y la mioglobina son hemoproteínas que juegan un papel fundamental en el organismo ya que participan en el transporte de oxígeno. Sin embargo, debido a su estructura química, estas moléculas pueden ejercer efectos deletéreos cuando se liberan al torrente sanguíneo de forma masiva, como sucede en determinadas condiciones patológicas asociadas a rabdomiólisis o hemólisis intravascular. Una vez en el plasma, estas hemoproteínas se pueden filtrar y acumular en el riñón, donde resultan citotóxicas, principalmente para el epitelio tubular, e inducen fracaso renal agudo y enfermedad renal crónica. En la presente revisión analizaremos los distintos contextos patológicos que provocan la acumulación renal de estas hemoproteínas, su relación con la pérdida de función renal a corto y largo plazo, los mecanismos fisiopatólogicos responsables de sus efectos adversos y los sistemas de defensa que contrarrestan tales acciones. Por último, describiremos los distintos tratamientos utilizados actualmente y mostraremos nuevas opciones terapéuticas basadas en la identificación de nuevas dianas celulares y moleculares, prestando especial atención a los diversos ensayos clínicos que se encuentran en marcha en la actualidad (AU)


Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body. However, because of their chemical structure, these molecules can exert harmful effects when they are released massively into the bloodstream, as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis. Once in the plasma, these haem proteins can be filtered and can accumulate in the kidney, where they become cytotoxic, particularly for the tubular epithelium, inducing acute kidney failure and chronic kidney disease. In this review, we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins, their relation to both acute and chronic loss of renal function, the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions. Finally, we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets, with particular emphasis on the numerous clinical trials that are currently ongoing (AU)


Assuntos
Humanos , Hemeproteínas/efeitos adversos , Hemeproteínas/uso terapêutico , Falência Renal Crônica/complicações , Estresse Oxidativo , Hemoglobinúria/etiologia , Rabdomiólise/etiologia , Insuficiência Renal Crônica/fisiopatologia , Morte Celular , Fibrose/complicações , Hemopexina/análise , Hemopexina/uso terapêutico
16.
J Pathol ; 244(3): 296-310, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29205354

RESUMO

Recurrent and massive intravascular haemolysis induces proteinuria, glomerulosclerosis, and progressive impairment of renal function, suggesting podocyte injury. However, the effects of haemoglobin (Hb) on podocytes remain unexplored. Our results show that cultured human podocytes or podocytes isolated from murine glomeruli bound and endocytosed Hb through the megalin-cubilin receptor system, thus resulting in increased intracellular Hb catabolism, oxidative stress, activation of the intrinsic apoptosis pathway, and altered podocyte morphology, with decreased expression of the slit diaphragm proteins nephrin and synaptopodin. Hb uptake activated nuclear factor erythroid-2-related factor 2 (Nrf2) and induced expression of the Nrf2-related antioxidant proteins haem oxygenase-1 (HO-1) and ferritin. Nrf2 activation and Hb staining was observed in podocytes of mice with intravascular haemolysis. These mice developed proteinuria and showed podocyte injury, characterized by foot process effacement, decreased synaptopodin and nephrin expression, and podocyte apoptosis. These pathological effects were enhanced in Nrf2-deficient mice, whereas Nrf2 activation with sulphoraphane protected podocytes against Hb toxicity both in vivo and in vitro. Supporting the translational significance of our findings, we observed podocyte damage and podocytes stained for Hb, HO-1, ferritin and phosphorylated Nrf2 in renal sections and urinary sediments of patients with massive intravascular haemolysis, such as atypical haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria. In conclusion, podocytes take up Hb both in vitro and during intravascular haemolysis, promoting oxidative stress, podocyte dysfunction, and apoptosis. Nrf2 may be a potential therapeutic target to prevent loss of renal function in patients with intravascular haemolysis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Injúria Renal Aguda/metabolismo , Anemia Hemolítica/metabolismo , Apoptose , Hemoglobinas/metabolismo , Podócitos/metabolismo , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Adulto , Anemia Hemolítica/genética , Anemia Hemolítica/patologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Endocitose , Feminino , Ferritinas/metabolismo , Heme Oxigenase-1/metabolismo , Hemólise , Humanos , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 Relacionado a NF-E2/genética , Fator 1 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Fosforilação , Podócitos/ultraestrutura , Receptores de Superfície Celular/metabolismo , Adulto Jovem
17.
Nefrologia (Engl Ed) ; 38(1): 13-26, 2018.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28668175

RESUMO

Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body. However, because of their chemical structure, these molecules can exert harmful effects when they are released massively into the bloodstream, as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis. Once in the plasma, these haem proteins can be filtered and can accumulate in the kidney, where they become cytotoxic, particularly for the tubular epithelium, inducing acute kidney failure and chronic kidney disease. In this review, we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins, their relation to both acute and chronic loss of renal function, the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions. Finally, we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets, with particular emphasis on the numerous clinical trials that are currently ongoing.


Assuntos
Injúria Renal Aguda/etiologia , Hemeproteínas/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/terapia , Proteínas Sanguíneas/fisiologia , Ensaios Clínicos como Assunto , Drogas em Investigação/uso terapêutico , Hemólise , Humanos , Quelantes de Ferro/uso terapêutico , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Estresse Oxidativo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Rabdomiólise/complicações , Rabdomiólise/metabolismo , Bicarbonato de Sódio/uso terapêutico , Terapias em Estudo
18.
Curr Med Chem ; 24(33): 3583-3605, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28494744

RESUMO

BACKGROUND: Renal disease is a serious health problem, with increasing incidence and prevalence. Oxidative stress and inflammation play a key role in the pathogenesis and progression of renal disease. Therefore, therapeutic approaches to decrease oxidative stress should be of interest. OBJECTIVE: This review aims to provide a comprehensive and updated overview of the protective mechanisms mediated by Nrf2 (nuclear factor erythroid 2-related factor 2), a description of novel compounds that target Nrf2, its effectiveness to prevent renal disease and the on-going clinical trials for this pathological condition. METHODS: We undertook a structured search of bibliographic databases for peer-reviewed research in literature about Nrf2 activators and renal disease. RESULTS: The transcription factor Nrf2 is an emerging regulator of cellular resistance to oxidants and inflammation. Nrf2 controls the basal and induced expression of a couple of cytoprotective and antiinflammatory genes that regulate the physiological and pathophysiological outcomes of oxidant exposure. We have analyzed numerous findings showing that Nrf2 induction protects against oxidative stress and modulates inflammation in acute kidney injury and chronic kidney disease progression. However, few clinical trials have been performed in humans. Recent studies suggested that renoprotective effects of Nrf2 activation are observed at low doses, whereas harmful effects appear at higher concentrations. CONCLUSION: The findings of this review confirm that novel studies are necessary to address whether Nrf2-targeting may be a safe therapeutic approach to decrease renal disease progression in humans.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Descoberta de Drogas , Rim/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Rim/metabolismo , Rim/patologia , Terapia de Alvo Molecular , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais/efeitos dos fármacos
19.
J Vis Exp ; (116)2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27805599

RESUMO

There is increasing evidence suggesting the important role of inflammation and, subsequently, macrophages in the development and progression of renal disease. Macrophages are heterogeneous cells that have been implicated in kidney injury. Macrophages may be classified into two different phenotypes: classically activated macrophages (M1 macrophages), that release pro-inflammatory cytokines and promote fibrosis; and alternatively activated macrophages (M2 macrophages) that are associated with immunoregulatory and tissue-remodeling functions. These macrophage phenotypes need to be discriminated and analyzed to determine their contribution to renal injury. However, there are scarce studies reporting consistent phenotypic and functional information about macrophage subtypes in inflammatory renal disease models, especially in rats. This fact may be related to the limited macrophage markers used in rats, contrary to mice. Therefore, novel strategies are necessary to quantify and characterize the renal content of these infiltrating cells in a reliable way. This manuscript details a protocol for kidney digestion and further phenotypic and quantitative analysis of macrophages from rat kidneys by flow cytometry. Briefly, kidneys were incubated with collagenase and total macrophages were identified according to the dual presence of CD45 (leukocytes common antigen) and CD68 (PAN macrophage marker) in live cells.This was followed by surface staining of CD86 (M1 marker) and CD163 (M2 marker). Rat peritoneal macrophages were used as positive control for macrophage marker detection by flow cytometry. Our protocol resulted in low cellular mortality and allowed characterization of different intracellular and surface protein markers, thus limiting the loss of cellular integrity observed in other protocols. Moreover, this procedure allows the use of macrophages for further techniques, including cell sorting and mRNA or protein expression studies, among others.


Assuntos
Citometria de Fluxo , Rim , Macrófagos , Fenótipo , Animais , Biomarcadores , Citocinas , Inflamação , Camundongos , Ratos
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