RESUMO
Pendrin is a membrane transporter encoded by solute carrier family26A4 (SLC26A4). Mutations in this gene are known to cause hearing loss, and recent data from animal studies indicate a link between pendrin expression and hypertension; although, this association in humans is unclear. To clarify this issue, we investigated the influence of pendrin on blood pressure by analyzing demographic and biochemical data - including blood pressure and urinary electrolyte excretion - in patients with bi-allelic SLC26A4 mutations. Systolic and diastolic blood pressure and the left ventricular hypertrophy index were lower in subjects with pendrin mutations than in controls. In addition, fractional excretion of Na+ and Cl- was increased and serum renin, angiotensin I and II levels were higher in subjects with pendrin mutations as compared to controls. Thus, patients with impaired pendrin function are likely to be resistant to high blood pressure due to enhanced urinary Na+ /Cl- excretion. These results suggest that pendrin may regulate blood pressure through increased urinary salt excretion.
Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Hipertrofia Ventricular Esquerda/genética , Proteínas de Membrana Transportadoras/genética , Adolescente , Adulto , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Cloretos/urina , Eletrólitos/urina , Feminino , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Hipertensão/urina , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/urina , Masculino , Proteínas de Membrana Transportadoras/biossíntese , Mutação , Renina/sangue , Sódio/urina , Transportadores de Sulfato , Adulto JovemRESUMO
OBJECTIVES: Dietary fiber intake is associated with a lower risk of diabetes, cardiovascular disease, and cancer. However, it is unknown whether dietary fiber has a beneficial effect on preventing the development of chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Using the UK Biobank prospective cohort, 110,412 participants who completed at least one dietary questionnaire and had an estimated glomerular filtration rate ≥60 mL/min/1.73 m2, urinary albumin-to-creatinine ratio <30 mg/g, and no history of CKD were included. The primary exposure was total dietary fiber density, calculated by dividing the absolute amount of daily total fiber intake by total energy intake (g/1,000 kcal). We separately examined soluble and insoluble fiber densities as additional predictors. The primary outcome was incident CKD based on diagnosis codes. RESULTS: A total of 3,507 (3.2%) participants developed incident CKD during a median follow-up of 9.9 years. In a multivariable cause-specific model, the adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for incident CKD were 0.85 (0.77-0.94), 0.78 (0.70-0.86), and 0.76 (0.68-0.86), respectively, for the second, third, and highest quartiles of dietary fiber density (reference: lowest quartile). In a continuous model, the aHR for each +∆1.0g/1,000 kcal increase in dietary fiber density was 0.97 (95% CI, 0.95-0.99). This pattern of associations was similar for both soluble and insoluble fiber densities and did not differ across subgroups of sex, age, body mass index, hypertension, diabetes, smoking, and inflammation. CONCLUSION: Increased fiber intake was associated with a lower risk of CKD in this large well-characterized cohort.
Assuntos
Diabetes Mellitus , Insuficiência Renal Crônica , Humanos , Estudos Prospectivos , Bancos de Espécimes Biológicos , Fatores de Risco , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Taxa de Filtração Glomerular , Fibras na Dieta , Reino Unido/epidemiologiaRESUMO
AIMS/HYPOTHESIS: Translationally controlled tumour protein (TCTP) is thought to be involved in cell growth by regulating mTOR complex 1 (mTORC1) signalling. As diabetes characteristically induces podocyte hypertrophy and mTORC1 has been implicated in this process, TCTP may have a role in the pathogenesis of diabetes-induced podocyte hypertrophy. METHODS: We investigated the effects and molecular mechanisms of TCTP in diabetic mice and in high glucose-stimulated cultured podocytes. To characterise the role of TCTP, we conducted lentivirus-mediated gene silencing of TCTP both in vivo and in vitro. RESULTS: Glomerular production of TCTP was significantly higher in streptozotocin induced-diabetic DBA/2J mice than in control animals. Double-immunofluorescence staining for TCTP and synaptopodin revealed that podocyte was the principal cell responsible for this increase. TCTP knockdown attenuated the activation of mTORC1 downstream effectors and the overproduction of cyclin-dependent kinase inhibitors (CKIs) in diabetic glomeruli, along with a reduction in proteinuria and a decrease in the sizes of podocytes as well as glomeruli. In addition, knockdown of TCTP in db/db mice prevented the development of diabetic nephropathy, as indicated by the amelioration of proteinuria, mesangial expansion, podocytopenia and glomerulosclerosis. In accordance with the in vivo data, TCTP inhibition abrogated high glucose-induced hypertrophy in cultured podocytes, which was accompanied by the downregulation of mTORC1 effectors and CKIs. CONCLUSIONS/INTERPRETATION: These findings suggest that TCTP might play an important role in the process of podocyte hypertrophy under diabetic conditions via the regulation of mTORC1 activity and the induction of cell-cycle arrest.
Assuntos
Biomarcadores Tumorais/metabolismo , Crescimento Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/metabolismo , Podócitos/patologia , Animais , Quinases Ciclina-Dependentes/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Inativação Gênica , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Proteínas dos Microfilamentos/metabolismo , Complexos Multiproteicos , Podócitos/metabolismo , Proteínas/metabolismo , Serina-Treonina Quinases TOR , Proteína Tumoral 1 Controlada por TraduçãoRESUMO
AIMS: In patients with immunoglobulin A (IgA) nephropathy, postnatal renal outcomes vary depending on kidney function and proteinuria. However, whether a decrease in proteinuria prior to conception improves postnatal maternal renal outcomes is unknown. METHODS: This was a single-center retrospective study. A total of 52 pregnant women with biopsy-proven IgA nephropathy were enrolled in the study between January 2004 and December 2009. We collected data on proteinuria, which had been measured 1 year prior to conception, at conception, during pregnancy, and postnatally. The study outcomes included changes in estimated glomerular filtration rate (eGFR) and proteinuria. RESULTS: The median serum creatinine, eGFR, and proteinuria levels at conception were 0.8 (0.5 - 2.6) mg/dl, 91.2 (24.1 - 157.0) ml/min, 0.7 (0.0 - 3.5) g/g, respectively. Compared with values measured at conception, serum creatinine (0.8 - 1.0 mg/dl, p < 0.01) and proteinuria (0.7 - 1.5 g/g, p < 0.01) increased significantly postnatally, while eGFR decreased (91.2 - 77.8 ml/min, p < 0.01). In a multiple linear regression analysis, proteinuria at conception were independently associated with a faster decline in postnatal maternal eGFR (ß = 4.50, p < 0.05). In addition, a less decline in maternal eGFR was observed in patients with a reduction in proteinuria (> 30%) prior to pregnancy, compared with those with a less reduction (≤ 30%). As for newborn outcomes, preterm delivery, caesarean section, low birth weight < 2,500 g, and need for neonatal intensive care were 15.4%, 46.2%, 25.0% and 7.7%, respectively. CONCLUSIONS: This study showed that in women with IgA nephropathy, proteinuria was significantly associated with the deterioration of postnatal maternal renal outcomes. Our study also suggests that a strategy for reducing proteinuria prior to pregnancy is required to preserve kidney function after delivery.
Assuntos
Glomerulonefrite por IGA/fisiopatologia , Rim/fisiopatologia , Complicações na Gravidez/fisiopatologia , Proteinúria/complicações , Adulto , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea , Feminino , Taxa de Filtração Glomerular , Humanos , Recém-Nascido , Gravidez , Estudos RetrospectivosRESUMO
Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identify SMPDL3b as a modulator of insulin signaling and demonstrate that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD.
Assuntos
Antígenos CD/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nefropatias Diabéticas/patologia , Insulina/metabolismo , Receptor de Insulina/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Animais , Caveolina 1/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Ceramidas/metabolismo , Ceramidas/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Nefropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Podócitos/citologia , Podócitos/metabolismo , Isoformas de Proteínas/metabolismo , Transdução de Sinais , Resultado do TratamentoRESUMO
We propose the unique structure of highly dispersible single-walled carbon nanotubes (SWCNTs) in various solvents and polymers using the ZnO nano particle template. Buckled nanospring-shaped carbon nanotubes (NS-CNTs) were synthesized by a chemical reaction of ZnO nanoparticles with acid-treated SWCNTs and then dissolving ZnO through chemical etching. The unique structure of distorted hexagonal NS-CNTs encircled around ZnO nanoparticles was formed by the bending of SWCNTs caused by the agglomeration of chemically adsorbed Zn(OH)2, which is further crystallized as the polycrystalline ZnO inner core. The highly dispersible NS-CNTs could be incorporated in the poly[(vinylidenefluoride-co-trifluoroethylene] [P(VDF-TrFE)] copolymer, one of widely studied ferro- and piezo-electric polymer, up to the value of 15 wt% as nanofillers. The relative dielectric constant (K) of polymer nanocomposite, at 1 kHz, was greatly enhanced from 12.7 to the value of 62.5 at 11 wt% of NS-CNTs, corresponding to a 492% increase compared to that of pristine P(VDF-TrFE) with only a small dielectric loss tangent (D) of 0.1.
RESUMO
BACKGROUND: Although asymptomatic microscopic hematuria (MH) is a common finding in clinical practice, its long-term outcome remains unknown. AIM: This study evaluated the clinical implication of MH in the general population using a large-scale long-term longitudinal cohort database. METHODS: This study included 8719 participants from the Korean Genome and Epidemiology Study between 2001 and 2014. MH was defined as ≥5 red blood cells per high-power field in random urinalysis without evidence of pyuria. The primary study outcome measure was incident chronic kidney disease (CKD), defined as estimated glomerular filtration rate <60 ml min-1â 1.73â m-2. RESULTS: During a median follow-up of 11.7 years, CKD occurred in 677 (7.8%) subjects. In Cox regression after adjustment for multiple confounders, subjects with MH had a significantly higher risk of incident CKD than those without [hazard ratio (HR) 1.45, 95% confidence interval (CI) 1.12-1.87; P = 0.005]. Isolated MH without proteinuria was also a risk factor of incident CKD (HR 1.37, 95% CI 1.04-1.79; P = 0.023) and the risk was further increased in MH with concomitant proteinuria (HR 5.41, 95% CI 2.54-11.49; P < 0.001). In propensity score matching analysis after excluding subjects with proteinuria, multi-variable stratified Cox regression analysis revealed that subjects with isolated MH had a significantly higher risk of incident CKD than those without (HR 1.83, 95% CI 1.14-2.94; P = 0.012). CONCLUSION: The presence of MH is associated with an increased risk of incident CKD in the general population. Therefore, attentive follow-up is warranted in persons with MH for early detection of CKD.
Assuntos
Hematúria/complicações , Hematúria/epidemiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Adulto , Idoso , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Incidência , Coreia (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Proteinúria/complicações , Fatores de Risco , UrináliseRESUMO
Glomerular visceral epithelial cells, namely podocytes, are highly specialized cells and give rise to primary processes, secondary processes, and finally foot processes. The foot processes of neighboring podocytes interdigitate, leaving between them filtration slits. These are bridged by an extracellular substance, known as the slit diaphragm, which plays a major role in establishing size-selective barrier to protein loss. Furthermore, podocytes are known to synthesize matrix molecules to the glomerular basement membrane (GBM), including type IV collagen, laminin, entactin, and agrin. Because diabetic nephropathy is clinically characterized by proteinuria and pathologically by glomerular hypertrophy and GBM thickening with foot process effacement, podocytes have been the focus in the field of research on diabetic nephropathy. As a result, many investigations have demonstrated that the diabetic milieu per se, hemodynamic changes, and local growth factors such as transforming growth factor-beta and angiotensin II, which are considered mediators in the pathogenesis of diabetic nephropathy, induce directly and/or indirectly hypertrophy, apoptosis, and structural changes, and increase type IV collagen synthesis in podocytes. This review explores some of the structural and functional changes of podocytes under diabetic conditions and their role in the development and progression of diabetic nephropathy.
Assuntos
Nefropatias Diabéticas/fisiopatologia , Podócitos/patologia , Podócitos/fisiologia , Proliferação de Células , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Progressão da Doença , Humanos , Hipertrofia/patologia , Junções Intercelulares/patologia , Junções Intercelulares/fisiologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologiaRESUMO
A cDNA library was constructed with mRNA extracted from TMV resistant hot pepper plants 24 and 48 h after inoculation by TMV. The library was screened differentially with radio-labeled cDNA synthesized with mRNA from the leaves of either TMV-inoculated or mock-inoculated hot pepper plants. CaSAR8.2 clone was one of the clones isolated by this differential screening. The predicted amino acid sequence of CaSAR8.2 has a homology of 52% similarity to that of tobacco SAR8.2 genes. Southern blot analysis showed that a multigene family of CaSAR8.2 was present in the hot pepper genome. Transcripts homologous to CaSAR8.2 accumulated abundantly in the leaves and the flowers, but little in other tissues. CaSAR8.2 gene expression was induced by avirulent pathotype TMV-P0 inoculation but not by virulent TMV-P1.2 inoculation. Effects of exogenously applied abiotic elicitors on CaSAR8.2 expression were also examined. Salicylic acid and ethephon treatments caused a rapid accumulation of CaSAR8.2 transcripts in pepper leaves and methyl jasmonate treatment slightly induced the expression of CaSAR8.2. A strain of Xanthomonas campestris pv. vesicatoria (Xcv) that contains an avirulence gene avrBs2, was infiltrated into the leaves of a pepper cultivar containing the Bs2 resistance gene. A marked induction of CaSAR8.2 gene expression was observed in Xcv-infiltrated leaves. These results suggest possible roles of CaSAR8.2 as pathogenesis-related protein against varieties of pathogens including virus and bacteria.
Assuntos
Capsicum/genética , Capsicum/virologia , Proteínas de Plantas/genética , Vírus do Mosaico do Tabaco/patogenicidade , Sequência de Aminoácidos , Sequência de Bases , Capsicum/microbiologia , DNA Complementar/genética , DNA de Plantas/genética , Expressão Gênica , Genes de Plantas , Dados de Sequência Molecular , Família Multigênica , RNA Mensageiro/genética , RNA de Plantas/genética , Homologia de Sequência de Aminoácidos , Distribuição Tecidual , Nicotiana/genética , Xanthomonas campestris/patogenicidadeRESUMO
Hot pepper (Capsicum annuum) plants exhibit a hypersensitive response (HR) against infection by many tobamoviruses. A clone (CaPR-4) encoding a putative pathogenesis-related protein 4 was isolated by differential screening of a cDNA library prepared from resistant pepper plant leaves inoculated with tobacco mosaic virus (TMV) pathotype P0. The predicted amino acid sequence of CaPR-4 is very similar to those of other plant PR-4s. Southern blot analysis showed that small gene families of PR-4-related sequences were present in the pepper genome. Hot pepper cultivar Bugang, resistant to TMV-P0 and susceptible to TMV-P1.2, induced CaPR-4 expression by pathotype P0 inoculation in inoculated and systemic leaves, but not by pathotype P1.2. Effects of exogenously applied abiotic elicitors upon the CaPR-4 expression were also examined. The expression of the CaPR-4 gene was stimulated by methyl jasmonate (MeJA), ethephon and wounding treatment. However, application of salicylic acid (SA) did not trigger the expression. Evidence is emerging that jasmonic acid and ethylene play key roles in the SA-independent pathways of plant-pathogen interaction. Taken together, these results suggest that the CaPR-4 gene is one of the defense-related genes conferring resistance on pepper plants by the SA-independent pathway and the cross-talk between signaling compounds, jasmonic acid and ethylene could have a great regulatory potential in a plant's defense against TMV.
Assuntos
Capsicum/virologia , Proteínas de Plantas/genética , Plantas Medicinais , Vírus do Mosaico do Tabaco , Acetatos/farmacologia , Sequência de Bases , Capsicum/genética , Clonagem Molecular , Ciclopentanos/farmacologia , DNA Complementar , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/fisiologia , Imunidade Inata , Dados de Sequência Molecular , Compostos Organofosforados/farmacologia , Oxilipinas , Reguladores de Crescimento de Plantas/farmacologia , RNA Mensageiro , Homologia de Sequência de AminoácidosRESUMO
A case of adult acute lymphoblastic leukaemia is reported. A 35-year-old male presented with an osteolytic lesion of the mandible. There was no definitive involvement in other craniofacial bones. A panoramic radiograph taken 4 months previously showed no bony involvement. A complete blood count showed a slightly decreased red blood cell count, but normal white blood cell count, white blood cell differential count and platelet count. Routine chemistry revealed hypercalcemia with an increased level of parathyroid hormone-related protein. Histopathological examination of bone marrow biopsy confirmed the diagnosis of acute lymphoblastic leukaemia.
Assuntos
Doenças Mandibulares/diagnóstico , Osteólise/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adulto , Perda do Osso Alveolar/diagnóstico , Diagnóstico Diferencial , Evolução Fatal , Humanos , Hipercalcemia/diagnóstico , Masculino , Imagem Multimodal , Proteína Relacionada ao Hormônio Paratireóideo/sangue , Tomografia por Emissão de Pósitrons , Radiografia Panorâmica , Tomografia Computadorizada por Raios XAssuntos
Ciclosporina/uso terapêutico , Homocisteína/sangue , Hiper-Homocisteinemia/epidemiologia , Imunossupressores/uso terapêutico , Transplante de Rim/fisiologia , Eritrócitos/metabolismo , Ácido Fólico/sangue , Humanos , Hiper-Homocisteinemia/sangue , Transplante de Rim/imunologia , Pessoa de Meia-Idade , Valores de Referência , Vitamina B 12/sangueRESUMO
The autocrine and paracrine activation of the renin-angiotensin system (RAS) within cells of the kidney plays a role in the overall pathophysiology of the renal disease due to diabetes. In this study, we focus on components of the RAS in the podocyte as these cells are important in the pathogenesis of glomerulosclerosis and proteinuria. Immortalized mouse podocytes were exposed to media containing normal glucose (NG) or high glucose (HG) for in vitro studies. In vivo studies utilized kidney tissue obtained from rats treated for 3 months with streptozotocin to induce diabetes. Angiotensinogen (AGT) and the angiotensin II (AII) type 1 receptor mRNA and protein were significantly increased in the podocytes cultured under the high glucose conditions. Both angiotensins I and II levels were significantly higher in cell lysates and the conditioned media of cells grown in high glucose. There were no differences in renin activity, angiotensin-converting enzyme level, or AII type 2 receptor level. Glomerular AGT and AII type 1 receptor assessed by means of immunohistochemistry were increased in diabetic rats compared with the control rats. Other measured components of the RAS within the glomeruli were not different. We suggest that increased AGT, an attendant increase in AII and increased AII type 1 receptor in podocytes experiencing diabetic conditions play an important role in the pathogenesis of diabetic nephropathy.