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1.
Sci Rep ; 11(1): 16843, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413390

RESUMO

Elevated angiotensin-converting enzyme 2 (ACE2) expression in organs that are potential targets of severe acute respiratory syndrome coronavirus 2 may increase the risk of coronavirus disease 2019 (COVID-19) infection. Previous reports show that ACE2 alter its tissue-specific expression patterns under various pathological conditions, including renal diseases. Here, we examined changes in pulmonary ACE2 expression in two mouse chronic kidney disease (CKD) models: adenine-induced (adenine mice) and aristolochic acid-induced (AA mice). We also investigated changes in pulmonary ACE2 expression due to renin-angiotensin system (RAS) blocker (olmesartan) treatment in these mice. Adenine mice showed significant renal functional decline and elevated blood pressure, compared with controls. AA mice also showed significant renal functional decline, compared with vehicles; blood pressure did not differ between groups. Renal ACE2 expression was significantly reduced in adenine mice and AA mice; pulmonary expression was unaffected. Olmesartan attenuated urinary albumin excretion in adenine mice, but did not affect renal or pulmonary ACE2 expression levels. The results suggest that the risk of COVID-19 infection may not be elevated in patients with CKD because of their stable pulmonary ACE2 expression. Moreover, RAS blockers can be used safely in treatment of COVID-19 patients with CKD.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , SARS-CoV-2/fisiologia , Adenina , Enzima de Conversão de Angiotensina 2/genética , Animais , Ácidos Aristolóquicos , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Imidazóis/administração & dosagem , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Tetrazóis/administração & dosagem
2.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206780

RESUMO

Vascular calcification (VC) is a risk factor for cardiovascular events and mortality in chronic kidney disease (CKD). Several components influence the occurrence of VC, among which inflammation. A novel uremic toxin, lanthionine, was shown to increase intracellular calcium in endothelial cells and may have a role in VC. A group of CKD patients was selected and divided into patients with a glomerular filtration rate (GFR) of <45 mL/min/1.73 m2 and ≥45 mL/min/1.73 m2. Total Calcium Score (TCS), based on the Agatston score, was assessed as circulating lanthionine and a panel of different cytokines. A hemodialysis patient group was also considered. Lanthionine was elevated in CKD patients, and levels increased significantly in hemodialysis patients with respect to the two CKD groups; in addition, lanthionine increased along with the increase in TCS, starting from one up to three. Interleukin IL-6, IL-8, and Eotaxin were significantly increased in patients with GFR < 45 mL/min/1.73 m2 with respect to those with GFR ≥ 45 mL/min/1.73 m2. IL-1b, IL-7, IL-8, IL-12, Eotaxin, and VEGF increased in calcified patients with respect to the non-calcified. IL-8 and Eotaxin were elevated both in the low GFR group and in the calcified group. We propose that lanthionine, but also IL-8 and Eotaxin, in particular, are a key feature of VC of CKD, with possible marker significance.


Assuntos
Alanina/análogos & derivados , Citocinas/sangue , Insuficiência Renal Crônica/metabolismo , Sulfetos/sangue , Calcificação Vascular/metabolismo , Adulto , Alanina/sangue , Biomarcadores/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Calcificação Vascular/sangue , Calcificação Vascular/etiologia
3.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299112

RESUMO

Patients with chronic kidney disease (CKD) are at increased risk of atherosclerosis and premature mortality, mainly due to cardiovascular events. However, well-known risk factors, which promote "classical" atherosclerosis are alone insufficient to explain the high prevalence of atherosclerosis-related to CKD (CKD-A). The complexity of the molecular mechanisms underlying the acceleration of CKD-A is still to be defied. To obtain a holistic picture of these changes, comprehensive proteomic approaches have been developed including global protein profiling followed by functional bioinformatics analyses of dysregulated pathways. Furthermore, proteomics surveys in combination with other "omics" techniques, i.e., transcriptomics and metabolomics as well as physiological assays provide a solid ground for interpretation of observed phenomena in the context of disease pathology. This review discusses the comprehensive application of various "omics" approaches, with emphasis on proteomics, to tackle the molecular mechanisms underlying CKD-A progression. We summarize here the recent findings derived from global proteomic approaches and underline the potential of utilizing integrative systems biology, to gain a deeper insight into the pathogenesis of CKD-A and other disorders.


Assuntos
Aterosclerose/complicações , Biologia Computacional/métodos , Genômica/métodos , Metabolômica/métodos , Proteômica/métodos , Insuficiência Renal Crônica/patologia , Animais , Humanos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Biologia de Sistemas
4.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34202940

RESUMO

Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.


Assuntos
Terapia Biológica , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/transplante , Nefropatias/terapia , Células-Tronco Mesenquimais/metabolismo , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/terapia , Animais , Apoptose/efeitos dos fármacos , Terapia Biológica/métodos , Diferenciação Celular , Proliferação de Células/efeitos dos fármacos , Autorrenovação Celular , Fracionamento Químico , Gerenciamento Clínico , Suscetibilidade a Doenças , Exossomos/metabolismo , Humanos , Nefropatias/etiologia , Nefropatias/patologia , Células-Tronco Mesenquimais/citologia , Substâncias Protetoras , Insuficiência Renal/diagnóstico , Insuficiência Renal/etiologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia
5.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281243

RESUMO

BACKGROUND: Bisphenol A (BPA) is a ubiquitous environmental toxin that accumulates in chronic kidney disease (CKD). Our aim was to explore the effect of chronic exposition of BPA in healthy and injured kidney investigating potential mechanisms involved. METHODS: In C57Bl/6 mice, administration of BPA (120 mg/kg/day, i.p for 5 days/week) was done for 2 and 5 weeks. To study BPA effect on CKD, a model of subtotal nephrectomy (SNX) combined with BPA administration for 5 weeks was employed. In vitro studies were done in human proximal tubular epithelial cells (HK-2 line). RESULTS: Chronic BPA administration to healthy mice induces inflammatory infiltration in the kidney, tubular injury and renal fibrosis (assessed by increased collagen deposition). Moreover, in SNX mice BPA exposure exacerbates renal lesions, including overexpression of the tubular damage biomarker Hepatitis A virus cellular receptor 1 (Havcr-1/KIM-1). BPA upregulated several proinflammatory genes and increased the antioxidant response [Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme Oxygenase-1 (Ho-1) and NAD(P)H dehydrogenase quinone 1 (Nqo-1)] both in healthy and SNX mice. The autophagy process was modulated by BPA, through elevated autophagy-related gene 5 (Atg5), autophagy-related gene 7 (Atg7), Microtubule-associated proteins 1A/1B light chain 3B (Map1lc3b/Lc3b) and Beclin-1 gene levels and blockaded the autophagosome maturation and flux (p62 levels). This autophagy deregulation was confirmed in vitro. CONCLUSIONS: BPA deregulates autophagy flux and redox protective mechanisms, suggesting a potential mechanism of BPA deleterious effects in the kidney.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/farmacologia , Fenóis/efeitos adversos , Fenóis/farmacologia , Insuficiência Renal Crônica/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos Benzidrílicos/metabolismo , Linhagem Celular , Feminino , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Túbulos Renais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Fenóis/metabolismo , Insuficiência Renal Crônica/fisiopatologia
6.
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
7.
FASEB J ; 35(8): e21761, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245616

RESUMO

Uremic cardiomyopathy is a common complication in chronic kidney disease (CKD) patients, accounting for a high mortality rate. Several mechanisms have been proposed to link CKD and cardiac alterations; however, the early cardiac modifications that occur in CKD that may trigger cardiac remodeling and dysfunction remain largely unexplored. Here, in a mouse model of CKD induced by 5/6 nephrectomy, we first analyzed the early transcriptional and inflammatory changes that occur in the heart. Five days after 5/6 nephrectomy, RNA-sequencing showed the upregulation of 54 genes in the cardiac tissue of CKD mice and the enrichment of biological processes related to immune system processes. Increased cardiac infiltration of T-CD4+ lymphocytes, myeloid cells, and macrophages during early CKD was observed. Next, since CC chemokine ligand-8 (CCL8) was one of the most upregulated genes in the heart of mice with early CKD, we investigated the effect of acute and transient CCL8 inhibition on uremic cardiomyopathy severity. An increase in CCL8 protein levels was confirmed in the heart of early CKD mice. CCL8 inhibition attenuated the early infiltration of T-CD4+ lymphocytes and macrophages to the cardiac tissue, leading to a protection against chronic cardiac fibrotic remodeling, inflammation and cardiac dysfunction induced by CKD. Altogether, our data show the occurrence of transcriptional and inflammatory changes in the heart during the early phases of CKD and identify CCL8 as a key contributor to the early cardiac inflammatory state that triggers further cardiac remodeling and dysfunction in uremic cardiomyopathy.


Assuntos
Cardiomiopatias/metabolismo , Quimiocina CCL8/biossíntese , Miocárdio/metabolismo , Insuficiência Renal Crônica/metabolismo , Regulação para Cima , Uremia/metabolismo , Animais , Cardiomiopatias/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Miocárdio/patologia , Insuficiência Renal Crônica/patologia , Uremia/patologia
8.
Front Immunol ; 12: 714511, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290717

RESUMO

Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19.


Assuntos
COVID-19/sangue , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Lectinas/sangue , Insuficiência Renal Crônica/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , COVID-19/complicações , COVID-19/patologia , COVID-19/fisiopatologia , Estudos de Coortes , Proteínas do Sistema Complemento/imunologia , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/virologia , Índice de Gravidade de Doença
9.
Nat Commun ; 12(1): 4350, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272381

RESUMO

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.


Assuntos
Predisposição Genética para Doença , Taxa de Filtração Glomerular/genética , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Biomarcadores , Creatinina/sangue , Cistatinas/farmacologia , Bases de Dados Genéticas , Europa (Continente) , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Rim/fisiologia , Especificidade de Órgãos , Locos de Características Quantitativas , RNA-Seq , Insuficiência Renal Crônica/genética , Fatores de Risco , Análise de Célula Única
10.
Nat Biomed Eng ; 5(6): 533-545, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34131321

RESUMO

Regular screening for the early detection of common chronic diseases might benefit from the use of deep-learning approaches, particularly in resource-poor or remote settings. Here we show that deep-learning models can be used to identify chronic kidney disease and type 2 diabetes solely from fundus images or in combination with clinical metadata (age, sex, height, weight, body-mass index and blood pressure) with areas under the receiver operating characteristic curve of 0.85-0.93. The models were trained and validated with a total of 115,344 retinal fundus photographs from 57,672 patients and can also be used to predict estimated glomerulal filtration rates and blood-glucose levels, with mean absolute errors of 11.1-13.4 ml min-1 per 1.73 m2 and 0.65-1.1 mmol l-1, and to stratify patients according to disease-progression risk. We evaluated the generalizability of the models for the identification of chronic kidney disease and type 2 diabetes with population-based external validation cohorts and via a prospective study with fundus images captured with smartphones, and assessed the feasibility of predicting disease progression in a longitudinal cohort.


Assuntos
Aprendizado Profundo , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/estatística & dados numéricos , Fotografação/estatística & dados numéricos , Insuficiência Renal Crônica/diagnóstico por imagem , Retina/diagnóstico por imagem , Área Sob a Curva , Glicemia/metabolismo , Estatura , Índice de Massa Corporal , Peso Corporal , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Progressão da Doença , Feminino , Fundo de Olho , Taxa de Filtração Glomerular , Humanos , Masculino , Metadados/estatística & dados numéricos , Pessoa de Meia-Idade , Redes Neurais de Computação , Fotografação/métodos , Estudos Prospectivos , Curva ROC , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Retina/metabolismo , Retina/patologia
11.
Free Radic Biol Med ; 172: 530-540, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34174395

RESUMO

Vascular calcification is very commonly observed in patients with chronic kidney disease (CKD), but there is no efficient therapy available. Oxidative stress plays critical roles in the progression of vascular calcification. Celastrol (Cel), a natural constituent derived from Chinese herbals, exhibits anti-oxidative stress activity. Here, we investigated the effect of celastrol on vascular calcification using vascular smooth muscle cells (VSMCs), arterial rings and CKD rats. Alizarin red staining and gene expression analysis showed that Cel dose-dependently inhibited rat VSMC calcification and osteogenic differentiation. Similarly, ex vivo study revealed that Cel inhibited calcification of rat and human arterial rings. In addition, micro-computed tomography, alizarin red staining and calcium content analysis confirmed that Cel inhibited aortic calcification in CKD rats. Interestingly, Cel treatment increased the mRNA and protein levels of heme oxygenase-1 (HMOX-1), and reduced the levels of reactive oxygen species (ROS) in VSMCs. Furthermore, both pharmacological inhibition of HMOX-1 and knockdown of HMOX-1 by siRNA independently counteracted the inhibitory effect of Cel on vascular calcification. Moreover, knockdown of HMOX-1 prevented Cel treatment-mediated reduction in ROS levels. Finally, Cel treatment reduced Vitamin D3-induced aortic calcification in mice and this effect was blocked by HMOX-1 inhibitor ZnPP9. Collectively, our results suggest that up-regulation of HMOX-1 is required for the inhibitory effect of Cel on vascular calcification. Modulation of HMOX-1 may provide a novel strategy for the treatment of vascular calcification in CKD.


Assuntos
Insuficiência Renal Crônica , Calcificação Vascular , Animais , Células Cultivadas , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Camundongos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso , Osteogênese , Estresse Oxidativo , Triterpenos Pentacíclicos , Ratos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Regulação para Cima , Calcificação Vascular/etiologia , Calcificação Vascular/genética , Microtomografia por Raio-X
12.
Nutrients ; 13(5)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068841

RESUMO

Proteins, especially plant proteins, may reduce inflammation among adults with chronic kidney disease (CKD). This systematic review and meta-analysis were conducted to evaluate the effect protein types (animal or plant) have on inflammation markers (CRP, IL-6, TNF-α) among adults with varying stages of CKD. The Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) was conducted to identify articles from inception until January 2021, utilizing six databases. Controlled trials that compared the effects of different protein types were analyzed using random-effects meta-analysis. Quality assessment and risk of bias of the included articles were assessed by using Cochrane risk of bias instrument and ROBINS-I. Out of the 10 studies that met the criteria, there was a decreasing trend in CRP levels when consuming plant proteins compared to animal proteins among non-dialysis participants. There was a statistically significant decrease when comparing animal proteins to unspecified proteins in CRP levels among dialysis participants [Hedges' g = 2.11; 95% CI 1.12, 3.11; p ≤ 0.001], favoring unspecified proteins. Furthermore, animal proteins (eggs, red meat) showed increasing trends in CRP levels compared to whey protein isolate. Caution must be considered regarding these results as controlled, non-randomized, trials were included in the analysis, which may have contributed to high risk of bias. Future research should focus on protein types and the impact they have on kidney disease progression and inflammation markers.


Assuntos
Biomarcadores , Inflamação/metabolismo , Proteínas/metabolismo , Insuficiência Renal Crônica/metabolismo , Adulto , Animais , Bases de Dados Factuais , Humanos , Diálise Renal
13.
FASEB J ; 35(7): e21725, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34110636

RESUMO

Renal fibrosis leads to chronic kidney disease, which affects over 15% of the U.S. population. PAI-1 is highly upregulated in the tubulointerstitial compartment in several common nephropathies and PAI-1 global ablation affords protection from fibrogenesis in mice. The precise contribution of renal tubular PAI-1 induction to disease progression, however, is unknown and surprisingly, appears to be independent of uPA inhibition. Human renal epithelial (HK-2) cells engineered to stably overexpress PAI-1 underwent dedifferentiation (E-cadherin loss, gain of vimentin), G2/M growth arrest (increased p-Histone3, p21), and robust induction of fibronectin, collagen-1, and CCN2. These cells are also susceptible to apoptosis (elevated cleaved caspase-3, annexin-V positivity) compared to vector controls, demonstrating a previously unknown role for PAI-1 in tubular dysfunction. Persistent PAI-1 expression results in a loss of klotho expression, p53 upregulation, and increases in TGF-ßRI/II levels and SMAD3 phosphorylation. Ectopic restoration of klotho in PAI-1-transductants attenuated fibrogenesis and reversed the proliferative defects, implicating PAI-1 in klotho loss in renal disease. Genetic suppression of p53 reversed the PA1-1-driven maladaptive repair, moreover, confirming a pathogenic role for p53 upregulation in this context and uncovering a novel role for PAI-1 in promoting renal p53 signaling. TGF-ßRI inhibition also attenuated PAI-1-initiated epithelial dysfunction, independent of TGF-ß1 ligand synthesis. Thus, PAI-1 promotes tubular dysfunction via klotho reduction, p53 upregulation, and activation of the TGF-ßRI-SMAD3 axis. Since klotho is an upstream regulator of both PAI-1-mediated p53 induction and SMAD3 signaling, targeting tubular PAI-1 expression may provide a novel, multi-level approach to the therapy of CKD.


Assuntos
Células Epiteliais/metabolismo , Glucuronidase/metabolismo , Rim/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Insuficiência Renal Crônica/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular , Fibroblastos/metabolismo , Fibrose/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Fosforilação/fisiologia , Transdução de Sinais , Proteína Smad3/metabolismo , Regulação para Cima/fisiologia
14.
Nutrients ; 13(6)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063969

RESUMO

Potassium (K), the main cation inside cells, plays roles in maintaining cellular osmolarity and acid-base equilibrium, as well as nerve stimulation transmission, and regulation of cardiac and muscle functions. It has also recently been shown that K has an antihypertensive effect by promoting sodium excretion, while it is also attracting attention as an important component that can suppress hypertension associated with excessive sodium intake. Since most ingested K is excreted through the kidneys, decreased renal function is a major factor in increased serum levels, and target values for its intake according to the degree of renal dysfunction have been established. In older individuals with impaired renal function, not only hyperkalemia but also hypokalemia due to anorexia, K loss by dialysis, and effects of various drugs are likely to develop. Thus, it is necessary to pay attention to K management tailored to individual conditions. Since abnormalities in K metabolism can also cause lethal arrhythmia or sudden cardiac death, it is extremely important to monitor patients with a high risk of hyper- or hypokalemia and attempt to provide early and appropriate intervention.


Assuntos
Estado Nutricional/fisiologia , Potássio/metabolismo , Insuficiência Renal Crônica/metabolismo , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Hiperpotassemia/etiologia , Hiperpotassemia/metabolismo , Hipopotassemia/etiologia , Hipopotassemia/metabolismo , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Recomendações Nutricionais , Insuficiência Renal Crônica/complicações
15.
Nutrients ; 13(5)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063377

RESUMO

Deficiency of the micronutrient zinc is common in patients with chronic kidney disease (CKD). The aim of this review is to summarize evidence presented in literature for consolidation of current knowledge regarding zinc status in CKD patients, including those undergoing hemodialysis. Zinc deficiency is known to be associated with various risk factors for cardiovascular disease (CVD), such as increased blood pressure, dyslipidemia, type 2 diabetes mellitus, inflammation, and oxidative stress. Zinc may protect against phosphate-induced arterial calcification by suppressing activation of nuclear factor kappa light chain enhancer of activated B. Serum zinc levels have been shown to be positively correlated with T50 (shorter T50 indicates higher calcification propensity) in patients with type 2 diabetes mellitus as well as those with CKD. Additionally, higher intake of dietary zinc was associated with a lower risk of severe abdominal aortic calcification. In hemodialysis patients, the beneficial effects of zinc supplementation in relation to serum zinc and oxidative stress levels was demonstrated in a meta-analysis of 15 randomized controlled trials. Thus, evidence presented supports important roles of zinc regarding antioxidative stress and suppression of calcification and indicates that zinc intake/supplementation may help to ameliorate CVD risk factors in CKD patients.


Assuntos
Doenças Cardiovasculares/complicações , Insuficiência Renal Crônica/complicações , Zinco/sangue , Zinco/deficiência , Arteriosclerose , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Dislipidemias/complicações , Humanos , Hipertensão/complicações , Inflamação , Minerais/sangue , Estresse Oxidativo , Fosfatos/sangue , Diálise Renal , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/mortalidade , Fatores de Risco , Calcificação Vascular/sangue , Zinco/metabolismo
17.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070521

RESUMO

An effective strategy is highly desirable for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Thioredoxin-1 (Trx), a redox-active protein that has anti-oxidative and anti-inflammatory properties, would be a candidate for this but its short half-life limits its clinical application. In this study, we examined the renoprotective effect of long-acting Trx that is comprised of human albumin and Trx (HSA-Trx) against AKI to CKD transition. AKI to CKD mice were created by renal ischemia-reperfusion (IR). From day 1 to day 14 after renal IR, the recovery of renal function was accelerated by HSA-Trx administration. On day 14, HSA-Trx reduced renal fibrosis compared with PBS treatment. At the early phase of fibrogenesis (day 7), HSA-Trx treatment suppressed renal oxidative stress, pro-inflammatory cytokine production and macrophage infiltration, thus ameliorating tubular injury and fibrosis. In addition, HSA-Trx treatment inhibited G2/M cell cycle arrest and apoptosis in renal tubular cells. While renal Trx protein levels were decreased after renal IR, the levels were recovered by HSA-Trx treatment. Together, HSA-Trx has potential for use in the treatment of AKI to CKD transition via its effects of modulating oxidative stress and inflammation.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Tiorredoxinas/administração & dosagem , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/patologia , Tiorredoxinas/farmacologia
18.
Nutrients ; 13(5)2021 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-34065078

RESUMO

The kidney is a highly metabolically active organ that relies on specialized epithelial cells comprising the renal tubules to reabsorb most of the filtered water and solutes. Most of this reabsorption is mediated by the proximal tubules, and high amounts of energy are needed to facilitate solute movement. Thus, proximal tubules use fatty acid oxidation, which generates more adenosine triphosphate (ATP) than glucose metabolism, as its preferred metabolic pathway. After kidney injury, metabolism is altered, leading to decreased fatty acid oxidation and increased lactic acid generation. This review discusses how metabolism differs between the proximal and more distal tubular segments of the healthy nephron. In addition, metabolic changes in acute kidney injury and chronic kidney disease are discussed, as well as how these changes in metabolism may impact tubule repair and chronic kidney disease progression.


Assuntos
Injúria Renal Aguda/metabolismo , Açúcares da Dieta/metabolismo , Ácidos Graxos/metabolismo , Túbulos Renais/metabolismo , Insuficiência Renal Crônica/metabolismo , Progressão da Doença , Humanos , Túbulos Renais Proximais/metabolismo , Ácido Láctico/biossíntese , Oxirredução
19.
Lab Invest ; 101(9): 1197-1209, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34031539

RESUMO

Uremic toxin accumulation is one possible reason for alterations in hepatic drug metabolism in patients with chronic kidney disease (CKD). However, the types of uremic toxins and underlying mechanisms are poorly understood. In this study, we report the role of advanced oxidation protein products (AOPPs), a modified protein uremic toxin, in the downregulation of cytochromes P450 1A2 (CYP1A2) and P450 3A4 (CYP3A4) expression levels and activities. We found that AOPP accumulation in plasma in a rat CKD model was associated with decreased protein levels of CYP1A2 and CYP3A4. CYP1A2 and CYP3A4 metabolites (acetaminophen and 6ß-hydroxytestosterone, respectively,) in liver microsomes were also significantly decreased. In human hepatocytes, AOPPs significantly decreased CYP1A2 and CYP3A4 protein levels in a dose- and time-dependent manner and downregulated their activities; however, bovine serum albumin (BSA), a synthetic precursor of AOPPs, had no effect on these parameters. The effect of AOPPs was associated with upregulation of p-IKKα/ß, p-IκBα, p-NF-κB, and inflammatory cytokines protein levels and increases in p-IKKα/ß/IKKα, p-IκBα/IκBα, and p-NF-κB/NF-κB phosphorylation ratios. Further, NF-kB pathway inhibitors BAY-117082 and PDTC abolished the downregulatory effects of AOPPs. These findings suggest that AOPPs downregulate CYP1A2 and CYP3A4 expression and activities by increasing inflammatory cytokine production and stimulating NF-κB-mediated signaling. Protein uremic toxins, such as AOPPs, may modify the nonrenal clearance of drugs in patients with CKD by influencing metabolic enzymes.


Assuntos
Produtos da Oxidação Avançada de Proteínas/farmacologia , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP3A/metabolismo , Regulação para Baixo/efeitos dos fármacos , NF-kappa B/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Células Hep G2 , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
PLoS Biol ; 19(5): e3001230, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33945525

RESUMO

Obesity-related renal lipotoxicity and chronic kidney disease (CKD) are prevalent pathologies with complex aetiologies. One hallmark of renal lipotoxicity is the ectopic accumulation of lipid droplets in kidney podocytes and in proximal tubule cells. Renal lipid droplets are observed in human CKD patients and in high-fat diet (HFD) rodent models, but their precise role remains unclear. Here, we establish a HFD model in Drosophila that recapitulates renal lipid droplets and several other aspects of mammalian CKD. Cell type-specific genetic manipulations show that lipid can overflow from adipose tissue and is taken up by renal cells called nephrocytes. A HFD drives nephrocyte lipid uptake via the multiligand receptor Cubilin (Cubn), leading to the ectopic accumulation of lipid droplets. These nephrocyte lipid droplets correlate with endoplasmic reticulum (ER) and mitochondrial deficits, as well as with impaired macromolecular endocytosis, a key conserved function of renal cells. Nephrocyte knockdown of diglyceride acyltransferase 1 (DGAT1), overexpression of adipose triglyceride lipase (ATGL), and epistasis tests together reveal that fatty acid flux through the lipid droplet triglyceride compartment protects the ER, mitochondria, and endocytosis of renal cells. Strikingly, boosting nephrocyte expression of the lipid droplet resident enzyme ATGL is sufficient to rescue HFD-induced defects in renal endocytosis. Moreover, endocytic rescue requires a conserved mitochondrial regulator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α). This study demonstrates that lipid droplet lipolysis counteracts the harmful effects of a HFD via a mitochondrial pathway that protects renal endocytosis. It also provides a genetic strategy for determining whether lipid droplets in different biological contexts function primarily to release beneficial or to sequester toxic lipids.


Assuntos
Lipase/metabolismo , Gotículas Lipídicas/metabolismo , Insuficiência Renal Crônica/metabolismo , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Endocitose/fisiologia , Células Epiteliais/metabolismo , Ácidos Graxos/metabolismo , Humanos , Rim/patologia , Lipase/fisiologia , Gotículas Lipídicas/fisiologia , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Mitocôndrias/metabolismo , Obesidade/complicações , Insuficiência Renal Crônica/fisiopatologia , Triglicerídeos/metabolismo
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