Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.932
Filtrar
1.
Mol Med ; 25(1): 5, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760202

RESUMO

BACKGROUND: Damage to the endothelium due to ischemia reperfusion injury (IRI) leads to a disruption of the microvasculature, which could be influenced by angiopoietin 1 via its effects on endothelium. We investigated the physiological and therapeutic roles of angiopoietin 1 in renal IRI using angiopoietin 1 knockout and over-expression mice. METHODS: Renal IRI was induced by clamping the right renal artery seven days after left uninephrectomy for 25 min followed by reperfusion. A whole body angiopoietin 1 knockout was achieved by induction with tamoxifen. The renal tubule over-expression of angiopoietin 1 was induced by doxycycline. RESULTS: In the normal mice, the renal expression of angiopoietin 1 increased 7 days to 14 days after IRI. The angiopoietin 1 knockout caused a delay in the recovery of renal function, less tubular regeneration and more residual tubular necrosis. The endothelial density was lower and the VE-cadherin protein loss was greater in the knockout mice. The over-expression of angiopoietin 1 attenuated the tubular necrosis and renal function impairment 1 and 3 days after IRI. The loss of the endothelium was ameliorated in the over-expression mice. This protective effect was associated with the up-regulation of the gene expression of epidermal growth factor, hepatocyte growth factor, and insulin like growth factor-1 and less tubular apoptosis. The over-expression of angiopoietin 1 stimulated tumor necrosis factor-α, C-C chemokine receptor type 2 and CX3C chemokine receptor 1 inflammatory gene expression, but did not influence macrophage infiltration. CONCLUSIONS: Altogether, the augmentation and downregulation of angiopoietin 1 attenuated renal damage and impaired renal recovery, respectively, by influencing the survival/regeneration of the endothelium. The manipulation of angiopoietin 1 represents a novel therapeutic approach for the treatment of ischemic kidney injury.


Assuntos
Lesão Renal Aguda/fisiopatologia , Angiopoietina-1/fisiologia , Endotélio/fisiologia , Traumatismo por Reperfusão/fisiopatologia , Animais , Regulação para Baixo , Túbulos Renais/patologia , Túbulos Renais/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regeneração
2.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
3.
BMC Infect Dis ; 18(1): 645, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541481

RESUMO

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) caused by pathogenic hantaviruses in Europe and Asia is often characterized by acute kidney injury (AKI) with massive proteinuria. Renal filtration depends on the integrity of epithelial and endothelial monolayers in the tubular and glomerular apparatus. Tubular and glomerular cells represent target cells of hantavirus infection. However, the detailed mechanisms of renal impairment induced by hantaviruses are not well understood. METHODS: We analyzed the cellular consequences of hantavirus infection by measuring adhesion and migration capacity of human renal cells infected with Puumala (PUUV) or Hantaan (HTNV) virus. The impact of hantaviral nucleocapsid proteins (N proteins) on motility was examined by transfection of podocytes. RESULTS: Infection of kidney cells with hantavirus species PUUV and HTNV causes a significant reduction of migration capacity. The impaired motility depends on viral replication and transfection of podocytes with N protein of PUUV or HTNV reveals that the expression of N protein alone is sufficient to deteriorate podocyte function. The cellular effects are more pronounced for the more pathogenic HTNV than for PUUV that causes a milder form of HFRS. CONCLUSIONS: The direct impairment of migration capacity of renal cells by hantaviral N proteins may contribute substantially to proteinuria observed in the clinical picture of hantavirus infection.


Assuntos
Movimento Celular/fisiologia , Células Epiteliais/fisiologia , Células Epiteliais/virologia , Infecções por Hantavirus/patologia , Hantavirus/fisiologia , Rim/fisiologia , Rim/virologia , Animais , Células Cultivadas , Cercopithecus aethiops , Células Epiteliais/patologia , Hantavirus/patogenicidade , Humanos , Rim/patologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiologia , Glomérulos Renais/virologia , Túbulos Renais/patologia , Túbulos Renais/fisiologia , Túbulos Renais/virologia , Podócitos/patologia , Podócitos/fisiologia , Podócitos/virologia , Virus Puumala/fisiologia , Células Vero , Replicação Viral/fisiologia
4.
Physiol Rep ; 5(23)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29212860

RESUMO

Electrolyte disorders due to tubular disorders are rare, and knowledge about validated clinical diagnostic tools such as tubular function tests is sparse. Reference values for tubular function tests are based on studies with small sample size in young healthy volunteers. Patients with tubular disorders, however, frequently are older and can have a compromised renal function. We therefore evaluated four tubular function tests in individuals with different ages and renal function. We performed furosemide, thiazide, furosemide-fludrocortisone, and desmopressin tests in healthy individuals aged 18-50 years, healthy individuals aged more than 50 years and individuals with compromised renal function. For each tubular function test we included 10 individuals per group. The responses in young healthy individuals were in line with previously reported values in literature. The maximal increase in fractional chloride excretion after furosemide was below the lower limit of young healthy individuals in 5/10 older subjects and in 2/10 patients with compromised renal function. The maximal increase in fractional chloride excretion after thiazide was below the lower limit of young healthy individuals in 6/10 older subjects and in 7/10 patients with compromised renal function. Median maximal urine osmolality after desmopressin was 1002 mosmol/kg H2O in young healthy individuals, 820 mosmol/kg H2O in older subjects and 624 mosmol/kg H2O in patients with compromised renal function. Reference values for tubular function tests obtained in young healthy adults thus cannot simply be extrapolated to older patients or patients with compromised kidney function. Larger validation studies are needed to define true reference values in these patient categories.


Assuntos
Testes de Função Renal/normas , Túbulos Renais/fisiologia , Adolescente , Adulto , Fatores Etários , Antidiuréticos/urina , Cloretos/metabolismo , Desamino Arginina Vasopressina/urina , Diuréticos/urina , Feminino , Furosemida/urina , Humanos , Testes de Função Renal/métodos , Túbulos Renais/crescimento & desenvolvimento , Masculino , Pessoa de Meia-Idade , Valores de Referência , Eliminação Renal , Reabsorção Renal , Tiazidas/urina
5.
Curr Biol ; 27(20): 3120-3131.e4, 2017 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-29033332

RESUMO

Oriented cell division (OCD) and convergent extension (CE) shape developing renal tubules, and their disruption has been associated with polycystic kidney disease (PKD) genes, the majority of which encode proteins that localize to primary cilia. Core planar cell polarity (PCP) signaling controls OCD and CE in other contexts, leading to the hypothesis that disruption of PCP signaling interferes with CE and/or OCD to produce PKD. Nonetheless, the contribution of PCP to tubulogenesis and cystogenesis is uncertain, and two major questions remain unanswered. Specifically, the inference that mutation of PKD genes interferes with PCP signaling is untested, and the importance of PCP signaling for cystogenic PKD phenotypes has not been examined. We show that, during proliferative stages, PCP signaling polarizes renal tubules to control OCD. However, we find that, contrary to the prevailing model, PKD mutations do not disrupt PCP signaling but instead act independently and in parallel with PCP signaling to affect OCD. Indeed, PCP signaling that is normally downregulated once development is completed is retained in cystic adult kidneys. Disrupting PCP signaling results in inaccurate control of tubule diameter, a tightly regulated parameter with important physiological ramifications. However, we show that disruption of PCP signaling is not cystogenic. Our results suggest that regulating tubule diameter is a key function of PCP signaling but that loss of this control does not induce cysts.


Assuntos
Polaridade Celular/fisiologia , Túbulos Renais/fisiologia , Morfogênese , Doenças Renais Policísticas/fisiopatologia , Transdução de Sinais , Animais , Feminino , Túbulos Renais/fisiopatologia , Masculino , Camundongos
6.
Arch Environ Contam Toxicol ; 73(3): 401-409, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28819681

RESUMO

Cadmium (Cd) is the most potent nephrotoxic heavy metal and may affect bone; it also has a long biological half-life in the human body. This study was designed to assess the effect of environmental low-level Cd exposure on kidney function and bone in the general population. The subjects of this cross-sectional study were 1907 healthy Korean adults who had not been exposed to Cd occupationally. We analyzed the concentrations of Cd in the urine, markers of renal tubule damage, such as ß2-microglobulin (ß2-MG) and N-acetyl-ß-D-glucosaminidase (NAG) activity in the urine, calculated the estimated glomerular filtration rate (eGFR) using serum creatinine, and measured bone mineral density (BMD). Also, we analyzed malondialdehyde (MDA) levels in the urine. The geometric mean concentration of Cd in urine was higher in women (1.36 µg/g creatinine) than in men (0.82 µg/g creatinine). Urinary Cd was significantly positively correlated with urinary ß2-MG and NAG activity, whereas it was negatively correlated with eGFR and BMD. The risk of renal tubule damage was significantly associated with urine Cd level, and the association remained significant after controlling for various confounding variables. However, no association was observed between urinary Cd level and glomerular dysfunction or bone damage. The concentration of MDA was increased with urinary Cd level in a dose-dependent manner. These findings suggest that low-level environmental Cd exposure may cause microscopic damage to renal tubules through oxidative stress but might not impair kidney glomeruli or bones.


Assuntos
Cádmio/toxicidade , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/toxicidade , Nefropatias/induzido quimicamente , Túbulos Renais/efeitos dos fármacos , Acetilglucosaminidase/metabolismo , Adulto , Biomarcadores/metabolismo , Cádmio/metabolismo , Creatinina/metabolismo , Estudos Transversais , Poluentes Ambientais/metabolismo , Humanos , Nefropatias/epidemiologia , Túbulos Renais/fisiologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/fisiologia , República da Coreia/epidemiologia
7.
Hypertension ; 70(2): 324-333, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28607127

RESUMO

We investigated the significance of the primary cilia on the macula densa and thick ascending limb (TAL) in regulation of renal hemodynamics, sodium excretion, and blood pressure in this study. A tissue-specific primary cilia knock-out (KO) mouse line was generated by crossing NKCC2-Cre mice with IFT88-Δ/flox mice (NKCC2CRE; IFT88Δ/flox), in which the primary cilia were deleted from the macula densa and TAL. NO generation was measured with a fluorescent dye (4,5-diaminofluorescein diacetate) in isolated perfused juxtaglomerular apparatus. Deletion of the cilia reduced NO production by 56% and 42% in the macula densa and TAL, respectively. NO generation by the macula densa was inhibited by both a nonselective and a selective nitric oxide synthesis inhibitors, whereas TAL-produced NO was inhibited by a nonselective and not by a selective NO synthesis 1 inhibitor. The tubuloglomerular feedback response was enhanced in the KO mice both in vitro measured with isolated perfused juxtaglomerular apparatuses and in vivo measured with micropuncture. In response to an acute volume expansion, the KO mice exhibited limited glomerular filtration rate elevation and impaired sodium excretion compared with the wild-type mice. The mean arterial pressure measured with telemetry was the same for wild-type and KO mice fed a normal salt diet. After a high salt diet, the mean arterial pressure increased by 17.4±1.6 mm Hg in the KO mice. On the basis of these findings, we concluded that the primary cilia on the macula densa and TAL play an essential role in the control of sodium excretion and blood pressure.


Assuntos
Pressão Sanguínea/fisiologia , Cílios/fisiologia , Hemodinâmica/fisiologia , Eliminação Renal/fisiologia , Cloreto de Sódio/metabolismo , Animais , Retroalimentação Fisiológica , Taxa de Filtração Glomerular/fisiologia , Sistema Justaglomerular/fisiologia , Sistema Justaglomerular/fisiopatologia , Glomérulos Renais/fisiologia , Glomérulos Renais/fisiopatologia , Túbulos Renais/fisiologia , Túbulos Renais/fisiopatologia , Camundongos , Modelos Animais , Óxido Nítrico
8.
Chin J Physiol ; 60(2): 114-123, 2017 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-28468029

RESUMO

Protriptyline has been used as an antidepressant. Clinically it has been prescribed in the auxiliary treatment of cancer patients. However, its effect on Ca²âº signaling and related physiology is unknown in renal cells. This study examined the effect of protriptyline on cytosolic free Ca²âº concentrations ([Ca²âº]i) and viability in Madin-Darby canine kidney (MDCK) tubular cells. Protriptyline induced [Ca²âº]i rises concentration-dependently. The response was reduced by 20% by removing extracellular Ca²âº. Protriptyline-induced Ca²âº entry was not altered by protein kinase C (PKC) activity but was inhibited by 20% by three modulators of store-operated Ca²âº channels: nifedipine, econazole and SKF96365. In Ca²âº-free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor 2,5- di-tert-butylhydroquinone (BHQ) or thapsigargin partially inhibited protriptyline-evoked [Ca²âº]i rises. Conversely, treatment with protriptyline inhibited partially BHQ or thapsigargin-evoked [Ca²âº]i rises. Inhibition of phospholipase C (PLC) with U73122 did not change protriptyline-induced [Ca²âº]i rises. Protriptyline at 5-200 µM decreased cell viability, which was not reversed by pretreatment with the Ca²âº chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/ AM). Together, in MDCK cells, protriptyline induced [Ca²âº]i rises by evoking PLC-independent Ca²âº release from the endoplasmic reticulum and other unknown stores, and Ca²âº entry via PKCinsensitive store-operated Ca²âº entry. Protriptyline also caused Ca²âº-independent cell death.


Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Sobrevivência Celular/fisiologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/fisiologia , Protriptilina/administração & dosagem , Animais , Antidepressivos Tricíclicos/administração & dosagem , Sinalização do Cálcio/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Túbulos Renais/citologia , Células Madin Darby de Rim Canino
9.
J Am Soc Nephrol ; 28(8): 2322-2336, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28336721

RESUMO

Cell-cell communication via Wnt ligands is necessary in regulating embryonic development and has been implicated in CKD. Because Wnt ligands are ubiquitously expressed, the exact cellular source of the Wnts involved in CKD remains undefined. To address this issue, we generated two conditional knockout mouse lines in which Wntless (Wls), a dedicated cargo receptor that is obligatory for Wnt secretion, was selectively ablated in tubular epithelial cells or interstitial fibroblasts. Blockade of Wnt secretion by genetic deletion of Wls in renal tubules markedly inhibited myofibroblast activation and reduced renal fibrosis after unilateral ureteral obstruction. This effect associated with decreased activation of ß-catenin and downstream gene expression and preserved tubular epithelial integrity. In contrast, fibroblast-specific deletion of Wls exhibited little effect on the severity of renal fibrosis after obstructive or ischemia-reperfusion injury. In vitro, incubation of normal rat kidney fibroblasts with tubule-derived Wnts promoted fibroblast proliferation and activation. Furthermore, compared with kidney specimens from patients without CKD, biopsy specimens from patients with CKD also displayed increased expression of multiple Wnt proteins, predominantly in renal tubular epithelium. These results illustrate that tubule-derived Wnts have an essential role in promoting fibroblast activation and kidney fibrosis via epithelial-mesenchymal communication.


Assuntos
Fibroblastos/fisiologia , Túbulos Renais/fisiologia , Rim/patologia , Proteínas Wnt/fisiologia , Animais , Comunicação Celular , Proliferação de Células , Células Cultivadas , Fibroblastos/citologia , Fibrose/etiologia , Humanos , Túbulos Renais/metabolismo , Camundongos , Camundongos Knockout , Ratos , Proteínas Wnt/biossíntese , Via de Sinalização Wnt
10.
Eur Heart J ; 38(24): 1872-1882, 2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28329085

RESUMO

Increased neurohumoral stimulation resulting in excessive sodium avidity and extracellular volume overload are hallmark features of decompensated heart failure. Especially in case of concomitant renal dysfunction, the kidneys often fail to elicit effective natriuresis. While assessment of renal function is generally performed by measuring serum creatinine-a surrogate for glomerular filtration-, this only represents part of the nephron's function. Alterations in tubular sodium handling are at least equally important in the development of volume overload and congestion. Venous congestion and neurohumoral activation in advanced HF further promote renal sodium and water retention. Interestingly, early on, before clinical signs of heart failure are evident, intrinsic renal derangements already impair natriuresis. This clinical review discusses the importance of heart failure (HF) induced changes in different nephron segments. A better understanding of cardiorenal interactions which ultimately result in sodium avidity in HF might help to treat and prevent congestion in chronic and acute HF.


Assuntos
Síndrome Cardiorrenal/fisiopatologia , Sódio/metabolismo , Doença Aguda , Síndrome Cardiorrenal/tratamento farmacológico , Diuréticos/uso terapêutico , Taxa de Filtração Glomerular/fisiologia , Homeostase/fisiologia , Humanos , Glomérulos Renais/fisiologia , Túbulos Renais/fisiologia , Fenótipo , Circulação Renal/fisiologia , Insuficiência Renal Crônica/fisiopatologia , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico
11.
Curr Opin Nephrol Hypertens ; 26(3): 143-147, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28198735

RESUMO

PURPOSE OF REVIEW: The kidney is a highly complex organ and renal function depends on many factors, both extrinsic to the kidney and intrinsic. The kidney responds both to systemic hormonal and neuronal signals and to autocrine and paracrine factors produced within the renal tissue. Recently, there has been an increased emphasis on crosstalk in and between different compartments in the kidney. RECENT FINDINGS: Crosstalk in the kidney between different cellular compartments has added new and important understanding of renal function and the development of kidney disease. SUMMARY: Most of the literature cited concern glomerular crosstalk but also tubular and interstitial crosstalk are being reviewed. Mechanistic insight into the communication between the cells may help us find new targets for treating kidney disease.


Assuntos
Comunicação Celular/fisiologia , Nefropatias/fisiopatologia , Glomérulos Renais/fisiologia , Túbulos Renais/fisiologia , Rim/fisiologia , Animais , Humanos
12.
Acta Physiol (Oxf) ; 220(2): 229-237, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28112877

RESUMO

Autophagy is a fundamental cellular process that maintains normal function and structure of the cell. It can be induced during stress and serves as an adaptive response for cell survival. Normal kidneys have high metabolic demands yet are relatively hypoxic, especially in the medulla and papilla. Injury or ageing aggravates metabolic perturbation and activates autophagy in many types of renal cells. In the kidney, tubular epithelial cells consume the most energy due to active transport mechanisms and therefore are the most susceptible to injuries from hypoxic or low-energy states. This brief review will summarize current understandings of the biological function and molecular regulation of epithelial autophagy during tubular injury and repair.


Assuntos
Autofagia/fisiologia , Túbulos Renais/fisiologia , Animais , Células Epiteliais/metabolismo , Humanos , Túbulos Renais/lesões
13.
Kidney Int ; 91(2): 265-267, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28087003

RESUMO

Prior efforts to generate renal epithelial cells in vitro have relied on pluripotent or bone marrow-derived mesenchymal stem cells. A recent publication in Nature Cell Biology describes the generation of induced tubular epithelial cells from fibroblasts, potentially offering a novel platform for personalized drug toxicity screening and in vitro disease modeling. This report serves as a promising proof of principle study and opens future research directions, including the optimization of the reprogramming process, efficient translation to adult human fibroblasts, and the generation of highly specific functional renal cell types.


Assuntos
Diferenciação Celular , Células Epiteliais/fisiologia , Fibroblastos/fisiologia , Túbulos Renais/fisiologia , Nefrologia/métodos , Medicina de Precisão/métodos , Medicina Regenerativa/métodos , Engenharia Tecidual , Animais , Biomarcadores/metabolismo , Células Cultivadas , Reprogramação Celular , Técnicas de Reprogramação Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Camundongos , Fenótipo
14.
J Am Soc Nephrol ; 28(1): 34-46, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27798243

RESUMO

Over a decade ago, it was proposed that the regulation of tubular repair in the kidney might involve the recapitulation of developmental pathways. Although the kidney cannot generate new nephrons after birth, suggesting a low level of regenerative competence, the tubular epithelial cells of the nephrons can proliferate to repair the damage after AKI. However, the debate continues over whether this repair involves a persistent progenitor population or any mature epithelial cell remaining after injury. Recent reports have highlighted the expression of Sox9, a transcription factor critical for normal kidney development, during postnatal epithelial repair in the kidney. Indeed, the proliferative response of the epithelium involves expression of several pathways previously described as being involved in kidney development. In some instances, these pathways are also apparently involved in the maladaptive responses observed after repeated injury. Whether development and repair in the kidney are the same processes or we are misinterpreting the similar expression of genes under different circumstances remains unknown. Here, we review the evidence for this link, concluding that such parallels in expression may more correctly represent the use of the same pathways in a distinct context, likely triggered by similar stressors.


Assuntos
Rim/fisiologia , Organogênese , Regeneração , Lesão Renal Aguda/fisiopatologia , Animais , Regulação da Expressão Gênica , Humanos , Rim/embriologia , Rim/crescimento & desenvolvimento , Túbulos Renais/fisiologia , Organogênese/genética , Regeneração/genética , Transdução de Sinais
15.
Nat Rev Nephrol ; 12(12): 721-737, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27748389

RESUMO

Insulin resistance is a systemic disorder that affects many organs and insulin-regulated pathways. The disorder is characterized by a reduced action of insulin despite increased insulin concentrations (hyperinsulinaemia). The effects of insulin on the kidney and vasculature differ in part from the effects on classical insulin target organs. Insulin causes vasodilation by enhancing endothelial nitric oxide production through activation of the phosphatidylinositol 3-kinase pathway. In insulin-resistant states, this pathway is impaired and the mitogen-activated protein kinase pathway stimulates vasoconstriction. The action of insulin on perivascular fat tissue and the subsequent effects on the vascular wall are not fully understood, but the hepatokine fetuin-A, which is released by fatty liver, might promote the proinflammatory effects of perivascular fat. The strong association of salt-sensitive arterial hypertension with insulin resistance indicates an involvement of the kidney in the insulin resistance syndrome. The insulin receptor is expressed on renal tubular cells and podocytes and insulin signalling has important roles in podocyte viability and tubular function. Renal sodium transport is preserved in insulin resistance and contributes to the salt-sensitivity of blood pressure in hyperinsulinaemia. Therapeutically, renal and vascular insulin resistance can be improved by an integrated holistic approach aimed at restoring overall insulin sensitivity and improving insulin signalling.


Assuntos
Resistência à Insulina , Rim/irrigação sanguínea , Rim/metabolismo , Tecido Adiposo/fisiologia , Animais , Modelos Animais de Doenças , Endotélio/fisiologia , Humanos , Resistência à Insulina/fisiologia , Túbulos Renais/fisiologia , Síndrome Metabólica/terapia , Receptor Cross-Talk , Transdução de Sinais , Cloreto de Sódio na Dieta
16.
Sci Rep ; 6: 34624, 2016 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-27703192

RESUMO

The GDF11 expression pattern and its effect on organ regeneration after acute injury in the elderly population are highly controversial topics. In our study, GDF11/8 expression increased after kidney ischemia-reperfusion injury (IRI), and the relatively lower level of GDF11/8 in the kidneys of aged mice was associated with a loss of proliferative capacity and a decline in renal repair, compared to young mice. In vivo, GDF11 supplementation in aged mice increased vimentin and Pax2 expression in the kidneys as well as the percentage of 5-ethynyl-2'-deoxyuridine (EdU)-positive proximal tubular epithelial cells. GDF11 improved the renal repair, recovery of renal function, and survival of elderly mice at 72 h after IRI. Moreover, the addition of recombinant GDF11 to primary renal epithelial cells increased proliferation, migration, and dedifferentiation by upregulating the ERK1/2 pathway in vitro. Our study indicates that GDF11/8 in the kidney decreases with age and that GDF11 can increase tubular cell dedifferentiation and proliferation as well as improve tubular regeneration after acute kidney injury (AKI) in old mice.


Assuntos
Lesão Renal Aguda/metabolismo , Envelhecimento/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Diferenciação de Crescimento/metabolismo , Túbulos Renais/fisiologia , Sistema de Sinalização das MAP Quinases , Regeneração , Lesão Renal Aguda/patologia , Envelhecimento/patologia , Animais , Proteínas Morfogenéticas Ósseas/farmacologia , Desdiferenciação Celular , Movimento Celular , Proliferação de Células , Fatores de Diferenciação de Crescimento/farmacologia , Camundongos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
17.
Nephron ; 134(3): 191-194, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27577054

RESUMO

Kidney function has been traditionally identified with glomerular filtration rate (GFR). However, the kidney has multiple functions beyond filtration and a careful evaluation of its whole spectrum of activities should be carried out. Furthermore, the kidney presents a functional reserve capacity both at glomerular and tubular level. In presence of appropriate stimuli, patients with intact nephron mass can increase their GFR and tubular secretion. The difference between maximal capacity and baseline function represents the renal functional reserve (RFR). Glomerular and tubular kidney stress test may help to evaluate RFR and improve the clinicians' ability to better diagnose and prognosticate both acute and chronic kidney disease. © 2016 S. Karger AG, Basel.


Assuntos
Testes de Função Renal , Glomérulos Renais/fisiologia , Túbulos Renais/fisiologia , Humanos
18.
Microb Pathog ; 99: 87-94, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27521227

RESUMO

Shiga toxin (Stx)-producing Escherichia coli (STEC) causes post-diarrheal Hemolytic Uremic Syndrome (HUS), which is one of the most common causes of acute renal failure in children in Argentine. The aim of the present work was to study the effects of Shiga toxin type 2 (Stx2) on regenerative mechanisms of primary cultures of human cortical renal tubular epithelial cells (HRTEC) and three-dimensional (3D) cultures of HRTEC. Primary cultures of HRTEC were able to develop tubular structures when grown in matrigel, which showed epithelial cells surrounding a central lumen resembling the original renal tubules. Exposure to Stx2 inhibited tubulogenesis in 3D-HRTEC cultures. Moreover, a significant increase in apoptosis, and decrease in cell proliferation was observed in tubular structures of 3D-HRTEC exposed to Stx2. A significant reduction in cell migration and vimentin expression levels was observed in HRTEC primary cultures exposed to Stx2, demonstrating that the holotoxin affected HRTEC dedifferentiation. Furthermore, a decreased number of cells expressing CD133 progenitor marker was found in HRTEC cultures treated with Stx2. The CD133 positive cells also expressed the Stx receptor globotriaosylceramide, which may explain their sensitivity to Stx2. In conclusion, Stx2 affects the regenerative processes of human renal tubular epithelial cells in vitro, by inhibiting cell dedifferentiation mechanisms, as well as tubules restoration. The development of 3D-HRTEC cultures that resemble original human renal proximal tubules is a novel in vitro model to study renal epithelial repair mechanisms after injury.


Assuntos
Células Epiteliais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Toxina Shiga II/toxicidade , Apoptose , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/fisiologia , Humanos , Túbulos Renais/fisiologia , Técnicas de Cultura de Órgãos
19.
Proteomics ; 16(20): 2706-2717, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27452873

RESUMO

Kidney aging together with related renal disease had become a major clinical problem. Understanding the mechanisms of aging was important for suspending senescence and decreasing the incidence of aging-related diseases. In the present work, 24-month-old F344 rats were used as aging rats and 3-month-old rats were used as young controls. Senescence-associated-ß-galactosidase staining results showed that the degree of senescence in renal tubules was more severe than that in glomeruli. We performed quantitative LC-MS to assess the differential protein expression profiles of senescent glomeruli and tubules. Bioinformatics analysis showed that aging, response to oxidative stress, nucleotide metabolism, amine acid metabolism, and inflammatory response were common mechanisms of glomerulus and tubule senescence. Differentially expressed proteins network mediated Golgi vesicle transport, actin filament based process, and regulation of cell death were associated with tubule senescence. More importantly, we found that the changes of four and a half LIM protein 2 (FHL2) were opposite in senescent glomeruli and tubules, and FHL2 could regulate p16 by suppressing T-box 3, which was involved in regulation of senescence in glomeruli and tubules. In conclusion, we assessed the mechanisms of senescence in aging glomeruli and tubules, and the results yielded new insight into kidney senescence.


Assuntos
Envelhecimento , Glomérulos Renais/fisiologia , Túbulos Renais/fisiologia , Proteoma/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Linhagem Celular , Senescência Celular , Cromatografia Líquida , Inibidor p16 de Quinase Dependente de Ciclina/análise , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Glomérulos Renais/citologia , Glomérulos Renais/ultraestrutura , Túbulos Renais/citologia , Túbulos Renais/ultraestrutura , Proteínas com Homeodomínio LIM/análise , Proteínas com Homeodomínio LIM/metabolismo , Proteínas Musculares/análise , Proteínas Musculares/metabolismo , Estresse Oxidativo , Proteoma/análise , Proteômica , Ratos Endogâmicos F344 , Proteínas com Domínio T/análise , Proteínas com Domínio T/metabolismo , Espectrometria de Massas em Tandem , Fatores de Transcrição/análise , Fatores de Transcrição/metabolismo
20.
Kidney Int ; 90(3): 610-26, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27470679

RESUMO

Acute kidney injury (AKI) is exacerbated in C-reactive protein transgenic mice but alleviated in Smad3 knockout mice. Here we used C-reactive protein transgenic/Smad3 wild-type and C-reactive protein transgenic/Smad3 knockout mice to investigate the signaling mechanisms by which C-reactive protein promotes AKI. Serum creatinine was elevated, and the extent of tubular epithelial cell necrosis following ischemia/reperfusion-induced AKI was greater in C-reactive protein transgenics but was blunted when Smad3 was deleted. Exacerbation of AKI in C-reactive protein transgenics was associated with increased TGF-ß/Smad3 signaling and expression of the cyclin kinase inhibitor p27, but decreased phosphorylated CDK2 and expression of cyclin E. Concomitantly, tubular epithelial cell proliferation was arrested at the G1 phase in C-reactive protein transgenics with fewer cells entering the S-phase cell cycle as evidenced by fewer bromodeoxyuridine-positive cells. In contrast, the protection from AKI in C-reactive protein transgenic/Smad3 knockout mice was associated with decreased expression of p27 and promotion of CDK2/cyclin E-dependent G1/S transition of tubular epithelial cells. In vitro studies using tubular epithelial cells showed that C-reactive protein activates Smad3 via both TGF-ß-dependent and ERK/MAPK cross talk mechanisms, Smad3 bound directly to p27, and blockade of Smad3 or the Fc receptor CD32 prevented C-reactive protein-induced p27-dependent G1 cell cycle arrest. In vivo, treatment of C-reactive protein transgenics with a Smad3 inhibitor largely improved AKI outcomes. Thus, C-reactive protein may promote AKI by impairing tubular epithelial cell regeneration via the CD32-Smad3-p27-driven inhibition of the CDK2/cyclin E complex. Targeting Smad3 may offer a new treatment approach for AKI.


Assuntos
Lesão Renal Aguda/patologia , Proteína C-Reativa/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Túbulos Renais/fisiologia , Proteína Smad3/metabolismo , Lesão Renal Aguda/sangue , Animais , Proteína C-Reativa/genética , Linhagem Celular Tumoral , Proliferação de Células , Creatinina/sangue , Ciclina E/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Isoquinolinas/farmacologia , Túbulos Renais/citologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Fosforilação , Piridinas/farmacologia , Pirróis/farmacologia , Ratos , Receptores de IgG/metabolismo , Regeneração , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/genética , Fator de Crescimento Transformador beta/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA