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1.
Arch Endocrinol Metab ; 63(4): 427-437, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365625

RESUMO

OBJECTIVE: Chronic kidney disease (CKD) risk is inconsistent in the normal-weight, overweight, and obese individuals due to the heterogeneity of metabolic status. This meta-analysis aimed to examine the combined effects of body mass index (BMI) and metabolic status on CKD risk. MATERIALS AND METHODS: The MEDLINE, EMBASE, and Web of Knowledge databases were systematically searched up to March 2019 to identify all eligible studies investigating the CKD risk (defined as GFR < 60 mL/min per 1.73 m2 and/or microalbuminuria or proteinuria) associated with the body size phenotypes which are known as metabolically unhealthy normal-weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight, metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO). The classification of subjects in included studies as metabolically unhealthy was based on the presence of three components of metabolic syndrome. BMI categorization was based on the criteria of included studies. The risk estimates and 95% confidence intervals (CIs) were extracted and pooled using random effects analysis. RESULTS: A total of 9 prospective cohort studies with 128773 participants and 4797 incident cases were included in the meta-analysis. Compared with healthy normal-weight individuals as reference, MUNW and MHO subjects showed an increased risk for CKD events with a pooled RR of 1.58 (95% CI = 1.28-1.96) in MUNW and 1.55 (95% CI = 1.34-1.79) in MHO persons. Also, MHOW was at increased risk for CKD (RR = 1.34, 95% CI = 1.20-1.51). MUHO individuals were at the highest risk for the development of CKD (RR = 2.13, 95% CI = 1.66-2.72). CONCLUSIONS: Individuals with metabolic abnormality, although at normal-weight, have an increased risk for CKD. Healthy overweight and obese individuals had higher risk; refuting the notion that metabolically healthy overweight and obese phenotypes are benign conditions.


Assuntos
Peso Corporal/genética , Síndrome Metabólica/genética , Fenótipo , Insuficiência Renal Crônica/genética , Índice de Massa Corporal , Humanos , Síndrome Metabólica/metabolismo , Estudos Observacionais como Assunto , Insuficiência Renal Crônica/metabolismo , Risco
2.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
3.
Cell Physiol Biochem ; 52(6): 1484-1502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31099508

RESUMO

BACKGROUND/AIMS: The transient receptor potential cation channel subfamily C member 6 (TRPC6) is a Ca2+-permeable nonselective cation channel and has received recent attention because of its capability to promote chronic kidney disease (CKD). The aims of this study were (i) to examine whether deletion of TRPC6 impacts on renal fibrosis and inflammatory cell infiltration in an early CKD model of unilateral ureter obstruction (UUO) in mice; and (ii) whether TRPC6-deficiency as well as UUO affect the regulation of TRPC expression in murine kidneys. METHODS: Wild-type (WT), Trpc6-knockout (Trpc6-/-) and New Zealand obese (NZO) mice underwent sham operation or unilateral ureteral obstruction (UUO). The kidneys were harvested 7 days after surgery. We examined renal fibrosis and inflammatory cell infiltration by histological and immunohistochemical staining. The mRNA expression of TRPC members and markers of fibrosis and inflammation in kidney were assessed by using real-time quantitative reverse transcription PCR. RESULTS: Histological and immunohistochemical analyses revealed less inflammatory cell infiltration (F4/80 and CD3) in UUO kidneys of Trpc6-/- mice compared to UUO kidneys of WT mice as well as less fibrosis. Genomic deletion of TRPC6 also affected the expression of pro-fibrotic genes in UUO Trpc6-/- kidneys compared to UUO WT kidneys while the expression of pro-inflammatory genes did not differ. UUO caused marked up-regulation of Trpc6 and down-regulation of Trpc1 mRNA in kidneys of WT and NZO mice. Trpc3 mRNA expression was significantly elevated in kidneys of Trpc6-/- mice underwent UUO while the levels did not change in kidneys of neither WT nor in NZO mice underwent UUO. CONCLUSION: TRPC6 contributes to renal fibrosis and immune cell infiltration in the UUO mouse model. Therefore, inhibition of TRPC6 emerges as a promising novel therapeutic strategy for treatment of chronic kidney failure in chronic obstructive nephropathy. However, confounding genomic and non-genomic effects of other TRPC channels should be taken into consideration to fully comprehend the renoprotective potential of targeting TRPC6 therapeutically under chronic kidney damaging conditions.


Assuntos
Regulação da Expressão Gênica , Rim/patologia , Canais de Cátion TRPC/genética , Obstrução Ureteral/genética , Animais , Modelos Animais de Doenças , Fibrose , Deleção de Genes , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , RNA Mensageiro/análise , RNA Mensageiro/genética , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Regulação para Cima , Obstrução Ureteral/complicações , Obstrução Ureteral/patologia
4.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071929

RESUMO

(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-ß-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.


Assuntos
Alanina/análogos & derivados , Cálcio/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Sulfetos/farmacologia , Uremia/tratamento farmacológico , Alanina/química , Alanina/farmacologia , Aminoácidos Sulfúricos/efeitos dos fármacos , Aminoácidos Sulfúricos/metabolismo , Linhagem Celular , Cistationina beta-Sintase/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Sulfeto de Hidrogênio/metabolismo , MicroRNAs/genética , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Oxirredução , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Sulfetos/química , Uremia/genética , Uremia/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
5.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072046

RESUMO

Chronic kidney disease (CKD) is characterized by an oxidative stress status, driving some CKD-associated complications, even at the gastrointestinal level. Indoxyl Sulfate (IS) is a protein-bound uremic toxin, poorly eliminated by dialysis. This toxin is able to affect the intestinal system, but its molecular mechanism/s in intestinal epithelial cells (IECs) remain poorly understood. This study's aim was to evaluate the effect of IS (31.2-250 µM) on oxidative stress in IEC-6 cells and on the intactness of IECs monolayers. Our results indicated that IS enhanced oxidative cell damage by inducing reactive oxygen species (ROS) release, reducing the antioxidant response and affecting Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation as well its related antioxidant enzymes. In the wound healing assay model, IS reduced IEC-6 migration, slightly impaired actin cytoskeleton rearrangement; this effect was associated with connexin 43 alteration. Moreover, we reported the effect of CKD patients' sera in IEC-6 cells. Our results indicated that patient sera induced ROS release in IEC-6 cells directly related to IS sera content and this effect was reduced by AST-120 serum treatment. Results highlighted the effect of IS in inducing oxidative stress in IECs and in impairing the intactness of the IECs cell monolayer, thus significantly contributing to CKD-associated intestinal alterations.


Assuntos
Antioxidantes/farmacologia , Indicã/farmacologia , Intestinos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Carbono/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Conexina 43/genética , Células Epiteliais/efeitos dos fármacos , Humanos , Intestinos/patologia , Fator 2 Relacionado a NF-E2/genética , Óxidos/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Uremia/tratamento farmacológico , Uremia/metabolismo , Uremia/patologia
6.
Int J Mol Sci ; 20(10)2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31109090

RESUMO

Chronic kidney disease (CKD) is associated with atherogenic dyslipidemia. Our aim was firstly to investigate patterns of fatty acids (FA) composition through various stages of CKD, and secondly, to evaluate the effect of CKD-specific FA disturbances on the expression of genes related to lipid metabolism at a cellular level. Serum FA composition was analyzed in 191 patients with consecutive severity stages of CKD, and 30 healthy controls free from CKD. Next, HepG2 human hepatic cells were treated with major representatives of various FA groups, as well as with FA extracted from a mix of serums of controls and of CKD stage 5 patients. Across worsening stages of CKD severity, there was an increasing monounsaturated FA (MUFA) content. It was associated with a concomitant decrease in n-3 and n-6 polyunsaturated FA. The incubation of hepatocytes with FA from CKD patients (compared to that of healthy subjects), resulted in significantly higher mRNA levels of genes involved in FA synthesis (fatty acid synthase (FASN) increased 13.7 ± 3.5 times, stearoyl-CoA desaturase 1 (SCD1) increased 4.26 ± 0.36 times), and very low density lipoprotein (VLDL) formation (apolipoprotein B (ApoB) increased 7.35 ± 1.5 times, microsomal triacylglycerol transfer protein (MTTP) increased 2.74 ± 0.43 times). In conclusion, there were progressive alterations in serum FA composition of patients with CKD. These alterations may partly contribute to CKD hypertriglyceridemia by influencing hepatocyte expression of genes of lipid synthesis and release.


Assuntos
Dislipidemias/etiologia , Dislipidemias/metabolismo , Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Biomarcadores , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Humanos , Testes de Função Renal , Metabolismo dos Lipídeos , Lipogênese , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/genética , Transcriptoma
7.
Nefrología (Madrid) ; 39(2): 198-201, mar.-abr. 2019. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-181328

RESUMO

La gammapatía monoclonal de significado renal incluye todas las enfermedades renales causadas por una inmunoglobulina monoclonal secretada por un clon de célula B no maligno. Por definición, los pacientes con gammapatía monoclonal de significado renal no cumplen criterios de mieloma múltiple y la alteración hematológica es generalmente considerada gammapatía monoclonal de significado incierto. No obstante, la dolencia que pueden causar a nivel renal puede ser importante, requiriendo un tratamiento específico. El espectro de la gammapatía monoclonal de significado renal es amplio, incluyendo una entidad reciente como la nefropatía C3. El desarrollo de una nefropatía C3 en el contexto de una gammapatía monoclonal de significado renal tras el trasplante renal no es frecuente y hasta el momento ha sido poco descrita. A continuación presentamos 3 casos de nefropatía C3 asociados a una gammapatía monoclonal de aparición de novo tras el trasplante renal


Monoclonal gammopathy of renal significance includes all renal disorders caused by a monoclonal immunoglobulin secreted by a non-malignant B-cell clone. Patients with MGRS do not, by definition, meet criteria for multiple myeloma, with haematological disorders generally considered to be monoclonal gammopathy of undetermined significance. Nevertheless, the renal involvement can be serious and require specific treatment. Monoclonal gammopathy of renal significance is associated with a wide spectrum of disorders, including the recently discovered C3 glomerulopathy. Development of C3 glomerulopathy in the context of monoclonal gammopathy of renal significance after kidney transplantation is uncommon and very few cases have been published to date. We report on three cases of C3 glomerulopathy in the context of de novo monoclonal gammopathy after kidney transplantation


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Paraproteinemias/etiologia , Nefropatias/complicações , Insuficiência Renal Crônica/genética , Transplante de Rim/métodos , Glomerulonefrite/diagnóstico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Imunossupressão/métodos , Rituximab/administração & dosagem , Biópsia , Diagnóstico Precoce
9.
Nat Commun ; 10(1): 1906, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015506

RESUMO

Studying immune repertoire in the context of organ transplant provides important information on how adaptive immunity may contribute and modulate graft rejection. Here we characterize the peripheral blood immune repertoire of individuals before and after kidney transplant using B cell receptor sequencing in a longitudinal clinical study. Individuals who develop rejection after transplantation have a more diverse immune repertoire before transplant, suggesting a predisposition for post-transplant rejection risk. Additionally, over 2 years of follow-up, patients who develop rejection demonstrate a specific set of expanded clones that persist after the rejection. While there is an overall reduction of peripheral B cell diversity, likely due to increased general immunosuppression exposure in this cohort, the detection of specific IGHV gene usage across all rejecting patients supports that a common pool of immunogenic antigens may drive post-transplant rejection. Our findings may have clinical implications for the prediction and clinical management of kidney transplant rejection.


Assuntos
Linfócitos B/imunologia , Rejeição de Enxerto/imunologia , Hospedeiro Imunocomprometido , Transplante de Rim , Polimorfismo Genético/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Insuficiência Renal Crônica/imunologia , Adolescente , Adulto , Linfócitos B/patologia , Criança , Pré-Escolar , Células Clonais , Feminino , Expressão Gênica , Rejeição de Enxerto/genética , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/genética , Humanos , Lactente , Rim/imunologia , Rim/patologia , Rim/cirurgia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos B/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/cirurgia , Análise de Sequência de DNA
10.
Nat Commun ; 10(1): 1847, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015462

RESUMO

Chronic kidney disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.


Assuntos
Loci Gênicos , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Insuficiência Renal Crônica/genética , Feminino , Carga Global da Doença , Humanos , Rim/fisiopatologia , Masculino , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Medição de Risco/métodos , Fatores de Risco , Fatores Sexuais
11.
Kidney Int ; 95(4): 743-746, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30904063

RESUMO

Massively parallel sequencing technologies such as exome sequencing are increasingly applied across medicine. Connaughton et al. report a high diagnostic yield of exome sequencing among adults with hereditary nephropathy or nephropathy of unknown cause. Their findings support broader use of genomic sequencing in nephrology and highlight key associated questions, including how to identify those patients for whom testing is indicated, pinpoint pathogenic variants, and balance the resultant health care benefits and clinical follow-up burden.


Assuntos
Nefrologia , Insuficiência Renal Crônica/genética , Adulto , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
12.
J Agric Food Chem ; 67(10): 2839-2847, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30829482

RESUMO

Fu brick tea is a unique post-fermented dark tea product which undergoes controlled fermentation by "golden flower" fungus Eurotium cristatum. This study examined the effects of Fu brick tea aqueous extract (FTE) to alleviate insulin resistance, chronic kidney disease (CKD), and its regulatory mechanism in high fat diet (HFD)-induced obese rats. Sixteen-week administration of FTE at 400 mg/kg bw in rats significantly antagonized HFD-induced insulin resistance and CKD with elevations in serum leptin, TC, TG, LDL-C, blood urea nitrogen, uric acid, and creatinine levels, respectively ( p < 0.05). FTE treatment decreased the glomerular area, the thickness of basement membrane of renal tubules, and kidney fibrosis in HFD-fed rats. FTE alleviated insulin resistance through down-regulation of SIRP-α expression and activation of the insulin signaling Akt/GLUT4, FoxO1, and mTOR/S6K1 pathways in skeletal muscle. Furthermore, FTE prevented the HFD-caused kidney dysfunction and lipid or collagen accumulation, which was accompanied by the inhibition of GSK-3ß phosphorylation and the action of PI3K/Akt and nuclear accumulation of Nrf2 in kidney. These results indicated that FTE alleviated insulin resistance and CKD through modulating insulin signal transduction cascades in skeletal muscle and enhanced the Nrf2 expression in kidney.


Assuntos
Resistência à Insulina , Músculo Esquelético/metabolismo , Insuficiência Renal Crônica/dietoterapia , Chá/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Masculino , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Chá/química
13.
Cell Mol Life Sci ; 76(11): 2077-2091, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887097

RESUMO

Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.


Assuntos
Hiperfosfatemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Calcificação Vascular/metabolismo , Animais , Fosfatos de Cálcio/química , Fosfatos de Cálcio/metabolismo , Transdiferenciação Celular , Condrócitos/metabolismo , Condrócitos/patologia , Regulação da Expressão Gênica , Humanos , Hiperfosfatemia/complicações , Hiperfosfatemia/genética , Hiperfosfatemia/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patologia , Ligante RANK/genética , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Calcificação Vascular/complicações , Calcificação Vascular/genética , Calcificação Vascular/patologia
14.
Lipids Health Dis ; 18(1): 60, 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30851738

RESUMO

BACKGROUND: Chronic kidney disease (CKD) associates with complex lipoprotein disturbances resulting in high cardiovascular risk. Apolipoprotein E (APOE) is a polymorphic protein with three common isoforms (E2; E3; E4) that plays a crucial role in lipoprotein metabolism, including hepatic clearance of chylomicrons and very low-density lipoprotein (VLDL) remnants, and reverse cholesterol transport. It demonstrates anti-atherogenic properties but data concerning the link between polymorphism and level of APOE in CKD patients are inconclusive. The aim of our research was to assess the relationship between APOE gene polymorphism and APOE concentration and its redistribution among lipoproteins along with CKD progression. METHODS: 90 non-dialysed CKD patients were included into the study. Real time PCR was used for APOE genotyping. APOE level was measured in serum and in isolated lipoprotein fractions (VLDL; IDL + HDL; HDL). Kidney function was assessed using eGFR CKD-EPI formula. RESULTS: The population was divided into three APOE genotype subgroups: E2(ε2ε3), E3(ε3ε3) and E4(ε3ε4). The highest APOE level was observed for the E2 subgroup (p < 0.001). APOE concentration positively correlated with eGFR value in the E2 subgroup (r = 0.7, p < 0.001) but inversely in the E3 subgroup (r = - 0.29, p = 0.02).). A lower concentration of APOE in the E2 subgroup was associated with its diminished contents in HDL and IDL + LDL particles. In the E3 subgroup, the higher concentration of APOE was related to the increased number of non-HDL lipoproteins. CONCLUSION: In patients with CKD, APOE genotype as well as renal function are associated with the concentration of APOE and its redistribution among lipoprotein classes.


Assuntos
Apolipoproteínas E/sangue , Apolipoproteínas E/genética , Polimorfismo Genético , Insuficiência Renal Crônica/genética , Idoso , Feminino , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/fisiopatologia
15.
Biochimie ; 160: 172-182, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30890453

RESUMO

POSTN knockdown inhibits the formation of NLRP3 inflammasome in rat myocardium.Periostin (POSTN), an extracellular matrix protein, and peroxisome proliferator-activated receptor alpha (PPARα), a ligand-activated nuclear transcription factor, are reported to be involved in renal and cardiac dysfunction associated with chronic kidney disease (CKD), respectively. This study is performed to investigate how POSTN-PPARα axis affects the progress of CKD. In vivo, adenovirus particles containing POSTN short hairpin RNA (Ad-shPOSTN) were intravenously given to Sprague Dawley rats following 5/6 nephrectomy. The effects of Ad-shPOSTN on CKD and CKD-associated cardiovascular disease were evaluated. In vitro, NRK-52E renal tubular epithelial cells were infected with Ad-shPOSTN or Ad-POSTN (overexpression) to explore whether POSTN affected collagen deposition by regulating PPARα. We found that POSTN expression was upregulated, while PPARα was downregulated in the injured renal and left ventricular tissues of nephrectomized rats. Ad-shPOSTN improved renal function, prevented cardiac dysfunction, and attenuated organ fibrosis in nephrectomized rats. The expression levels of renal and myocardial PPARα were increased following Ad-shPOSTN administration. Furthermore, POSTN silencing suppressed the formation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in the myocardium: the levels of NLRP3, anti-apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase 1, mature interleukin (IL)-1ß and IL-18 were reduced. In NRK-52E cells, forced overexpression of POSTN directly inhibited PPARα expression and induced collagen deposition. WY14643, a PPARα agonist, suppressed POSTN-induced collagen deposition. In summary, our study demonstrates that POSTN negatively regulates PPARα expression. Targeting POSTN-PPARα axis may present a novel protective intervention to alleviate CKD and CKD-associated cardiac dysfunction.


Assuntos
Moléculas de Adesão Celular/metabolismo , Cardiopatias/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PPAR alfa/metabolismo , Insuficiência Renal Crônica/patologia , Animais , Moléculas de Adesão Celular/genética , Células Cultivadas , Cardiopatias/genética , Cardiopatias/metabolismo , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Nefrectomia , PPAR alfa/genética , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo
16.
Int J Mol Sci ; 20(3)2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30708974

RESUMO

Chronic kidney disease (CKD) leads to the loss of kidney function, as well as the dysfunction of several other organs due to the release of uremic toxins into the system. In a murine CKD model, reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress are increased in the hippocampus. Mesenchymal stem cells (MSCs) are one of the candidates for cell-based therapy for CKD; however severe pathophysiological conditions can decrease their therapeutic potential. To address these issues, we established tauroursodeoxycholic acid (TUDCA)-treated MSCs using MSCs isolated from patients with CKD (CKD-hMSCs) and assessed the survival and ROS generation of neural cell line SH-SY5Y cells by co-culturing with TUDCA-treated CKD-hMSCs. In the presence of the uremic toxin P-cresol, the death of SH-SY5Y cells was induced by ROS-mediated ER stress. Co-culture with TUDCA-treated CKD-hMSCs increased anti-oxidant enzyme activities in SH-SY5Y cells through the upregulation of the cellular prion protein (PrPC) expression. Upregulated PrPC expression in SH-SY5Y cells protected against CKD-mediated ER stress and apoptosis. In an adenine-induced murine CKD model, injection with TUDCA-treated CKD-hMSCs suppressed ROS generation and ER stress in the hippocampus. These results indicate that TUDCA-treated CKD-hMSCs prevent the CKD-mediated cell death of SH-SY5Y cells by inhibiting ER stress. Our study suggests that treatment with TUDCA could be a powerful strategy for developing autologous MSC-based therapeutics for patients with CKD, and that PrPC might be a pivotal target for protecting neural cells from CKD-mediated ER stress.


Assuntos
Adenina/efeitos adversos , Hipocampo/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Insuficiência Renal Crônica/terapia , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular , Técnicas de Cocultura , Cresóis/efeitos adversos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Proteínas PrPC/genética , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Regulação para Cima
18.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717170

RESUMO

Matrix Gla Protein (MGP), a small Gla vitamin K-dependent protein, is the most powerful natural occurring inhibitor of calcification in the human body. To become biologically active, MGP must undergo vitamin K-dependent carboxylation and phosphorylation. Vitamin K deficiency leads to the inactive uncarboxylated, dephosphorylated form of MGP (dpucMGP). We aimed to review the existing data on the association between circulating dpucMGP and vascular calcification, renal function, mortality, and cardiovascular disease in distinct populations. Moreover, the association between vitamin K supplementation and serum levels of dpucMGP was also reviewed.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Doenças Cardiovasculares/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Processamento de Proteína Pós-Traducional , Insuficiência Renal Crônica/metabolismo , Calcificação Vascular/metabolismo , Deficiência de Vitamina K/metabolismo , Vitamina K/metabolismo , Transporte Biológico , Proteínas de Ligação ao Cálcio/genética , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/mortalidade , Suplementos Nutricionais , Proteínas da Matriz Extracelular/genética , Regulação da Expressão Gênica , Humanos , Fosforilação , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/mortalidade , Análise de Sobrevida , Calcificação Vascular/complicações , Calcificação Vascular/genética , Calcificação Vascular/mortalidade , Rigidez Vascular , Deficiência de Vitamina K/complicações , Deficiência de Vitamina K/genética , Deficiência de Vitamina K/mortalidade
20.
J Am Soc Nephrol ; 30(2): 201-215, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30655312

RESUMO

BACKGROUND: Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. METHODS: To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children's Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. RESULTS: By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients. CONCLUSIONS: Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.


Assuntos
Transplante de Rim/métodos , Medicina de Precisão/métodos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/cirurgia , Sequenciamento Completo do Exoma/métodos , Adolescente , Boston , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Testes Genéticos/métodos , Rejeição de Enxerto , Sobrevivência de Enxerto , Hospitais Pediátricos , Humanos , Transplante de Rim/efeitos adversos , Masculino , Prognóstico , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Transplantados/estatística & dados numéricos , Resultado do Tratamento
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