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2.
J Clin Invest ; 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38842935

RESUMO

Proliferative glomerulonephritis is a severe condition often leading to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte population in lupus nephritis mouse models with decrease in the production of proinflammatory cytokines, autoantibodies and glomerular complement deposition, which are all characteristic features of PI3K delta (PI3Kδ) inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.

3.
Sci Transl Med ; 13(614): eabg0809, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34613809

RESUMO

Lymphatic cystic malformations are rare genetic disorders mainly due to somatic gain-of-function mutations in the PIK3CA gene. These anomalies are frequently associated with pain, inflammatory flares, esthetic deformities, and, in severe forms, life-threatening conditions. There is no approved medical therapy for patients with lymphatic malformations. In this proof-of-concept study, we developed a genetic mouse model of PIK3CA-related lymphatic malformations that recapitulates human disease. Using this model, we demonstrated the efficacy of alpelisib, an approved pharmacological inhibitor of PIK3CA in oncology, in preventing lymphatic malformation occurrence, improving lymphatic anomalies, and extending survival. On the basis of these results, we treated six patients with alpelisib, including three children, displaying severe PIK3CA-related lymphatic malformations. Patients were already unsuccessfully treated with rapamycin, percutaneous sclerotherapies, and debulking surgical procedures. We assessed the volume of lymphatic malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib administration was associated with improvements in the six patients. Previously intractable vascular malformations shrank, and pain and inflammatory flares were attenuated. MRI showed a decrease of 48% in the median volume of lymphatic malformations over 6 months on alpelisib. During the study, two patients developed adverse events potentially related to alpelisib, including grade 1 mucositis and diarrhea. In conclusion, this study supports PIK3CA inhibition as a promising therapeutic strategy in patients with PIK3CA-related lymphatic anomalies.


Assuntos
Tiazóis , Animais , Humanos , Camundongos
5.
Kidney Int ; 94(5): 912-925, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30021702

RESUMO

It is unclear whether long-term sodium-glucose cotransporter 2 (SGLT2) inhibition such as that during the treatment of diabetes has deleterious effects on the kidney. Therefore, we first sought to determine whether abnormal glucose metabolism occurs in the kidneys of 22-week-old BTBR ob/ob diabetic mice. Second, the cumulative effect of chronic SGLT2 inhibition by ipragliflozin and 30% calorie restriction, either of which lowered blood glucose to a similar extent, on renal glucose metabolism was evaluated. Mass spectrometry-based metabolomics demonstrated that these diabetic mice exhibited an abnormal elevation in the renal pools of tricarboxylic acid cycle metabolites. This was almost completely nullified by SGLT2 inhibition and calorie restriction. Moreover, imaging mass spectrometry indicated an increased level of the tricarboxylic acid cycle intermediate, citrate, in the cortex of the diabetic mice. SGLT2 inhibition as well as calorie restriction almost completely eliminated citrate accumulation in the cortex. Furthermore, imaging mass spectrometry revealed that the accumulation of oxidized glutathione in the cortex of the kidneys, prominent in the glomeruli, was also canceled by SGLT2 inhibition and calorie restriction. Effects of these beneficial interventions were consistent with improvements in glomerular damage, such as albuminuria, glomerular hyperfiltration, and mesangial expansion. Tubulointerstitial macrophage infiltration and fibrosis were ameliorated only by calorie restriction, which may have been due to autophagy activation, which was observed only with calorie restriction. Thus, chronic SGLT2 inhibition is efficient in normalizing the levels of accumulated tricarboxylic acid cycle intermediates and increased oxidative stress in the kidneys of diabetic mice.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Glucose/metabolismo , Glucosídeos/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Tiofenos/farmacologia , Animais , Glicemia/análise , Restrição Calórica , Ciclo do Ácido Cítrico/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Rim/metabolismo , Masculino , Camundongos , Camundongos Obesos
6.
Nature ; 558(7711): 540-546, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29899452

RESUMO

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Lipoma/tratamento farmacológico , Lipoma/enzimologia , Terapia de Alvo Molecular , Anormalidades Musculoesqueléticas/tratamento farmacológico , Anormalidades Musculoesqueléticas/enzimologia , Nevo/tratamento farmacológico , Nevo/enzimologia , Tiazóis/uso terapêutico , Malformações Vasculares/tratamento farmacológico , Malformações Vasculares/enzimologia , Adulto , Animais , Criança , Modelos Animais de Doenças , Feminino , Células HeLa , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Camundongos , Fenótipo , Escoliose/complicações , Escoliose/tratamento farmacológico , Sirolimo/uso terapêutico , Síndrome , Neoplasias Vasculares/complicações , Neoplasias Vasculares/tratamento farmacológico
7.
Physiol Rep ; 6(10): e13707, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29845768

RESUMO

Recent epidemiologic studies revealed a correlation between acute kidney injury (AKI) episodes and the progression to chronic kidney disease (CKD). Although the severity and duration of the initial insult likely predict the development of CKD, information regarding tissue markers predictive of early development of renal fibrosis is limited. We investigated key markers in fibrotic kidney in rats and mice. Seven- to eight-week-old male Sprague-Dawley rats underwent bilateral ischemia-reperfusion injury (IRI). Kidney tissues were collected to determine the markers correlated with the severity of kidney fibrosis. In a separate set, a specific chemokine (C-C motif) receptor 2 (CCR2) inhibitor, RS-102895, was administered to 9-week-old male C57BL/6J mice that underwent unilateral IRI (9.2 mg/kg/day in drinking water for 17 days) to investigate whether blockade of the monocyte chemotactic protein-1 (MCP-1) signaling was sufficient to prevent fibrosis. Among candidate tissue markers, neutrophil gelatinase-associated lipocalin (NGAL) and MCP-1 mRNA expressions were correlated with kidney fibrosis. Studies on macrophage polarity showed that mRNA expression of M2, but not M1 macrophage markers, were correlated with acute-phase serum creatinine and fibrosis. Pharmacological blockade of the MCP-1-CCR2 signaling downregulated CCR2, which was insufficient to improve fibrosis in mouse unilateral IRI model, suggesting that additional, redundant pathways contribute to fibrosis. These findings suggested that tissue NGAL expression and M2 macrophage markers are promising markers that show severity of kidney fibrosis. Mechanistic involvement of these markers in CKD pathogenesis warrant additional investigation.


Assuntos
Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Rim/metabolismo , Rim/patologia , Lipocalina-2/metabolismo , Macrófagos/metabolismo , Animais , Biomarcadores/metabolismo , Creatinina/sangue , Fibrose , Masculino , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores CCR2/metabolismo , Transdução de Sinais
9.
Sci Rep ; 7(1): 6516, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28747725

RESUMO

Obesity is a risk factor for many diseases including diabetes, cancer, cardiovascular disease, and chronic kidney disease. Obesity is characterized by the expansion of white adipose tissue (WAT). Hypertrophy and hyperplasia of adipocytes cause tissue hypoxia followed by inflammation and fibrosis. Its trigger, preadipocyte differentiation into mature adipocytes, is finely regulated by transcription factors, signal molecules, and cofactors. We found that echinomycin, a potent HIF-1 inhibitor, completely inhibited adipogenesis in 3T3-L1 WAT preadipocytes by affecting the early phase of mitotic clonal expansion. The dose required to exert the effect was surprisingly low and the time was short. Interestingly, its inhibitory effect was independent of HIF-1 pathways. Time-course DNA microarray analysis of drug-treated and untreated preadipocytes extracted a major transcription factor, CCAAT/enhancer-protein ß, as a key target of echinomycin. Echinomycin also inhibited adipogenesis and body weight gain in high fat diet mice. These findings highlight a novel role of echinomycin in suppressing adipocyte differentiation and offer a new therapeutic strategy against obesity and diabetes.


Assuntos
Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Proteína beta Intensificadora de Ligação a CCAAT/antagonistas & inibidores , Equinomicina/farmacologia , Inibidores Enzimáticos/farmacologia , Células 3T3-L1 , Animais , Fármacos Antiobesidade/administração & dosagem , Peso Corporal , Equinomicina/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Perfilação da Expressão Gênica , Camundongos , Análise em Microsséries , Fatores de Tempo
10.
Kidney Int ; 92(1): 154-164, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28318627

RESUMO

Vascular adhesion protein-1 (VAP-1) is a unique molecule since it acts as an adhesion molecule as well as an ectoenzyme catalyzing oxidative deamination of primary amines and generates hydrogen peroxide in the extracellular space. While VAP-1 is implicated in various inflammatory diseases, its role in acute kidney injury is less characterized. Here we studied VAP-1 expression in the kidney and the effect of its inhibition in a rat model of renal ischemia/reperfusion injury. VAP-1 was predominantly expressed in pericytes, which released enzymatically active enzyme. In vivo, a specific VAP-1 inhibitor, RTU-1096, significantly ameliorated rat renal ischemia/reperfusion injury and decreased neutrophil infiltration measured 12 hours after injury without altering macrophage or T lymphocyte populations. The protective effect of VAP-1 inhibition was lost in neutrophil-depleted rats, suggesting its inhibition ameliorated renal ischemia/reperfusion injury by suppressing neutrophil infiltration. To investigate whether hydrogen peroxide generated by VAP-1 enzyme reaction enhances neutrophil infiltration, we conducted an under-agarose migration assay with purified human neutrophils. Recombinant human VAP-1 significantly induced neutrophil migration, which was almost completely inhibited by RTU-1096 or catalase. Thus, VAP-1 plays a critical role in the pathophysiology of renal ischemia/reperfusion injury by enhancement of neutrophil infiltration generating a local hydrogen peroxide gradient. Hence, VAP-1 inhibition may be a novel therapy in ischemic acute kidney injury.


Assuntos
Amina Oxidase (contendo Cobre)/metabolismo , Moléculas de Adesão Celular/metabolismo , Peróxido de Hidrogênio/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Pericitos/metabolismo , Traumatismo por Reperfusão/metabolismo , Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Animais , Moléculas de Adesão Celular/antagonistas & inibidores , Modelos Animais de Doenças , Humanos , Rim/patologia , Nefropatias/patologia , Nefropatias/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Comunicação Parácrina , Pericitos/patologia , Ratos Sprague-Dawley , Ratos Wistar , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais , Fatores de Tempo
11.
Nephron ; 135(3): 201-206, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27960172

RESUMO

AST-120 (kremezin; Kureha Chemical, Tokyo, Japan) is an oral spherical carbonaceous adsorbent, which was approved for clinical use in Japanese chronic kidney disease (CKD) patients in 1991. It adsorbs indole, the precursor of indoxyl sulfate, in the intestines and prevents indoxyl sulfate production. Indoxyl sulfate, initially identified as a major uremic toxin that causes uremic symptoms, contributes to CKD progression. Since AST-120 decreases serum indoxyl sulfate in a dose-dependent manner, multicenter prospective trials have been conducted in Japan in the 1980s; these trials were mostly in favor of the efficacy of AST-120 in delaying the initiation of dialysis in patients with advanced stage CKD. Many animal studies support the effects of AST-120 on renal outcomes as well as on cardiovascular complications. However, there are yet no reports that unequivocally demonstrate the improvement of hard renal endpoints and/or cardiovascular endpoints. This commentary briefly reviews the major outcomes of the recent clinical trials on AST-120.


Assuntos
Carbono/uso terapêutico , Óxidos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Adsorção , Animais , Ensaios Clínicos como Assunto , Humanos , Indicã/metabolismo , Japão , Insuficiência Renal Crônica/metabolismo , Toxinas Biológicas/metabolismo
12.
Am J Physiol Renal Physiol ; 308(8): F878-87, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25656369

RESUMO

Dipeptidyl peptidase (DPP)-4 is an enzyme that cleaves and inactivates incretin hormones capable of stimulating insulin secretion from pancreatic ß-cells. DPP-4 inhibitors are now widely used for the treatment of type 2 diabetes. Experimental studies have suggested a renoprotective role of DPP-4 inhibitors in various models of diabetic kidney disease, which may be independent of lowering blood glucose levels. In the present study, we examined the effect of DPP-4 inhibitors in the rat Thy-1 glomerulonephritis model, a nondiabetic glomerular injury model. Rats were injected with OX-7 (1.2 mg/kg iv) and treated with the DPP-4 inhibitor alogliptin (20 mg·kg(-1)·day(-1)) or vehicle for 7 days orally by gavage. Alogliptin significantly reduced the number of CD68-positive inflammatory macrophages in the kidney, which was associated with a nonsignificant tendency to ameliorate glomerular injury and reduce proteinuria. Another DPP-4 inhibitor, anagliptin (300 mg·kg(-1)·day(-1) mixed with food) and a glucagon-like peptide-1 receptor agonist, exendin-4 (10 mg/kg sc), similarly reduced CD68-positive macrophage infiltration to the kidney. Furthermore, ex vivo transmigration assays using peritoneal macrophages revealed that exendin-4, but not alogliptin, dose dependently reduced monocyte chemotactic protein-1-stimulated macrophage infiltration. These data suggest that DPP-4 inhibitors reduced macrophage infiltration directly via glucagon-like peptide-1-dependent signaling in the rat Thy-1 nephritis model and indicate that the control of inflammation by DPP-4 inhibitors is useful for the treatment of nondiabetic kidney disease models.


Assuntos
Anti-Inflamatórios/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Glomerulonefrite/prevenção & controle , Glomérulos Renais/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Uracila/análogos & derivados , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Soro Antilinfocitário , Linhagem Celular , Quimiocina CCL2/farmacologia , Quimiotaxia/efeitos dos fármacos , Citoproteção , Modelos Animais de Doenças , Exenatida , Glomerulonefrite/enzimologia , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glomérulos Renais/enzimologia , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Masculino , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia , Proteinúria/enzimologia , Proteinúria/imunologia , Proteinúria/prevenção & controle , Ratos Sprague-Dawley , Receptores de Glucagon/agonistas , Receptores de Glucagon/metabolismo , Transdução de Sinais/efeitos dos fármacos , Uracila/farmacologia , Peçonhas/farmacologia
13.
Kidney Int ; 88(2): 262-75, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25692954

RESUMO

Tubulointerstitial hypoxia plays a critical role in the pathogenesis of kidney injury, and hypoxia-inducible factor (HIF)-1 is a master regulator of cellular adaptation to hypoxia. Aside from oxygen molecules, factors that modify HIF-1 expression and functional operation remain obscure. Therefore, we sought to identify novel HIF-1-regulating genes in kidney. A short-hairpin RNA library consisting of 150 hypoxia-inducible genes was derived from a microarray analysis of the rat renal artery stenosis model screened for the effect on HIF-1 response. We report that CCAAT/enhancer-binding protein δ (CEBPD), a transcription factor and inflammatory response gene, is a novel HIF-1 regulator in kidney. CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys. In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1ß in a nuclear factor-κB-dependent manner, which not only increased HIF-1α expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1α. Thus our study provides novel insight into HIF-1 regulation in tubular epithelial cells and offers a potential hypoxia and inflammation link relevant in both acute and chronic kidney diseases.


Assuntos
Proteína delta de Ligação ao Facilitador CCAAT/genética , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Hipóxia/metabolismo , Rim/patologia , Nefrite/metabolismo , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/genética , Angiopoietinas/metabolismo , Animais , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Células Cultivadas , Cisplatino/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Expressão Gênica , Técnicas de Silenciamento de Genes , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Hipóxia/etiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mediadores da Inflamação/farmacologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , NF-kappa B/metabolismo , Nefrectomia/efeitos adversos , Nefrite/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Obstrução da Artéria Renal/complicações , Traumatismo por Reperfusão/complicações , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Transcrição Gênica , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
J Ren Nutr ; 25(2): 160-3, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25556149

RESUMO

Patients with advanced chronic kidney disease are exposed to uremic toxins. In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. Indoxyl sulfate (IS) increases oxygen consumption in tubules, aggravating hypoxia of the kidney, and progression of the kidney disease. IS also induces endoplasmic reticulum stress and thereby contributes the progression of cellular damages in tubular epithelial cells. Hypoxia-inducible factor (HIF) is a master transcriptional regulator of adaptive responses against hypoxia and regulates expression of erythropoietin (EPO). IS suppresses EPO expression via HIF-dependent and HIF-independent manner. IS impedes the recruitment of transcriptional coactivators to HIF via upregulation of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 through a mechanism of posttranscriptional messenger RNA stabilization. Furthermore, IS induces activating transcription factor 4 via endoplasmic reticulum stress, decreasing EPO expression. Although erythropoiesis-stimulating agent (ESA) resistance is generally defined as lack of responses to exogenous ESA administration, suppression of endogenous production of EPO under uremic conditions may aggravate ESA resistance. Uremia is associated with increased formation of advanced glycation end products (AGE). Studies of transgenic rats overexpressing glyoxalse 1 (GLO1), which detoxifies precursors of advanced glycation end products, demonstrated that glycative stress causes renal senescence and vascular endothelial dysfunction. Glycative stress also suppresses HIF activation making the kidney susceptible to hypoxia as a final common pathway to end-stage kidney disease.


Assuntos
Eritropoese/fisiologia , Diálise Renal , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Uremia/fisiopatologia , Humanos , Insuficiência Renal Crônica/complicações , Uremia/complicações
15.
F1000Res ; 42015.
Artigo em Inglês | MEDLINE | ID: mdl-26937272

RESUMO

Chronic kidney disease (CKD) is defined as any condition that causes reduced kidney function over a period of time. Fibrosis, tubular atrophy and interstitial inflammation are the hallmark of pathological features in CKD. Regardless of initial insult, CKD has some common pathways leading CKD to end-stage kidney disease, including hypoxia in the tubulointerstitium and proteinuria. Recent advances in genome editing technologies and stem cell research give great insights to understand the pathogenesis of CKD, including identifications of the origins of renal myofibroblasts and tubular epithelial cells upon injury. Environmental factors such as hypoxia, oxidative stress, and epigenetic factors in relation to CKD are also discussed.

16.
FASEB J ; 27(10): 4059-75, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23792300

RESUMO

Chronic hypoxia in the tubulointerstitium serves as a final common pathway in progressive renal disease. Circumstantial evidence suggests that hypoxia-inducible factor (HIF)-1 in the ischemic tubules may be functionally inhibited in a chronic kidney disease (CKD) milieu. In this study, we hypothesized that indoxyl sulfate (IS), a uremic toxin, impairs the cellular hypoxic response. In human kidney (HK-2) proximal tubular cells, IS reduced the hypoxic induction of HIF-1 target genes. This effect was not associated with quantitative changes in the HIF-1α protein, but with functional impairment of the HIF-1α C-terminal transactivation domain (CTAD). Among factors that impeded the recruitment of transcriptional coactivators to the HIF-1αCTAD, IS markedly up-regulated Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) through a mechanism of post-transcriptional mRNA stabilization involving the extracellular signal-regulated kinase (ERK) 1/2 pathway. In vivo, disproportionate expression of HIF target genes was demonstrated in several CKD models, which was offset by an oral adsorbent, AST-120. Furthermore, administration of indole reduced the induction of angiogenic, hypoxia-inducible genes in rats with experimental heart failure. Results of these studies reveal a novel role of IS in modulating the transcriptional response of HIF-1 and provide insight into molecular mechanisms underlying progressive nephropathies as well as cardiovascular complications.


Assuntos
Fator 1 Induzível por Hipóxia/metabolismo , Indicã/farmacologia , RNA Mensageiro/metabolismo , Insuficiência Renal Crônica/metabolismo , Uremia/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Animais , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Fator 1 Induzível por Hipóxia/genética , Camundongos , RNA Mensageiro/genética , Ratos , Transdução de Sinais/fisiologia , Fatores de Transcrição de p300-CBP/genética
17.
J Biol Chem ; 287(42): 34866-34882, 2012 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-22908232

RESUMO

Anthracycline chemotherapeutic agents of the topoisomerase inhibitor family are widely used for the treatment of various tumors. Although targeted tumor tissues are generally situated in a hypoxic environment, the connection between efficacy of anthracycline agents and cellular hypoxia response has not been investigated in depth. Here, we report that doxorubicin (DXR) impairs the transcriptional response of the hypoxia-inducible factor (HIF) by inhibiting the binding of the HIF heterodimer to the consensus -RCGTG- enhancer element. This pleiotropic effect retarded migration of von Hippel-Lindau (VHL)-defective renal cell carcinoma and that of VHL-competent renal cell carcinoma in hypoxia. This effect was accompanied by a coordinated down-regulation of HIF target lysyl oxidase (LOX) family members LOX, LOX-like2 (LOXL2), and LOXL4. Furthermore, DXR suppressed HIF target genes in tumor xenografts, inhibited cardiac induction of HIF targets in rats with acute anemia, and impaired the angiogenic response in the isoproterenol-induced heart failure model, which may account for the clinical fragility of doxorubicin cardiomyopathy. Collectively, these findings highlight the impaired hypoxia response by anthracycline agents affecting both tumors and organs of the cancer host and offer a promising opportunity to develop HIF inhibitors using DXR as a chemical template.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/metabolismo , Cardiomiopatias/metabolismo , Movimento Celular/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/metabolismo , Aminoácido Oxirredutases/biossíntese , Animais , Antibióticos Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/patologia , Hipóxia Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Células HeLa , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Miocárdio/metabolismo , Miocárdio/patologia , Transplante de Neoplasias , Neovascularização Patológica/patologia , Proteína-Lisina 6-Oxidase , Ratos , Ratos Sprague-Dawley , Elementos de Resposta , Transplante Heterólogo
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