RESUMO
PURPOSE: The main aim was to map serum levels of IL-1/IL-6 family cytokines and relevant receptors from serum samples taken across treatment in patients with Renal Cell Carcinoma (RCC). Additionally, we explored the possible interactions between these measurements, immunohistochemistry and intratumoral blood flow. METHODS: We included 40 patients undergoing open surgery for renal tumors. Blood samples were collected before, during (taken simultaneously from a peripheral site and the renal vein (RV) before clamping) and after surgery. Samples were analyzed for IL-6, IL-27, IL-31, OSM, TNF-α, serum (s)-gp130, s-IL-6Rα, s-IL-33R, IL-1Rα and VEGF. All 35 RCC tumors were histologically subtyped as clear cell (CCRCC), papillary or chromophobe. Immunohistochemistry for the CCRCC group included expression of IL-6/IL-6R. Intratumoral blood flow was determined by calculating intratumoral contrast enhancement on preoperative computerized tomography (CT) imaging. RESULTS: In the CCRCC patients, the intraoperative RV concentration of IL-6 was significantly higher than in both the preoperative and postoperative samples (p = 0.005 and p = 0.032, respectively). Furthermore, the intraoperative ratio showed significantly higher levels of IL-6 in the RV than in the simultaneously drawn peripheral sample. Immunohistochemistry showed general expression of IL-6 (23/24) in both tumor cells and the vasculature (20/23). Moreover, s-IL-6R was expressed in tumor cells in 23/24 studied patients. Increased blood flow in the CCRCC tumors predicted increased IL-6 levels in the RV (p < 0.001). The other cytokines and receptors showed an overall stability across the measurements. However, the intraoperative ratios of IL-33R and gp130 showed significantly higher levels in the RV. CONCLUSION: Serum levels of IL-6 increased during surgery. Intraoperative IL-6 and s-IL-33R values were higher in the RV compared to the periphery, suggesting secretion from the tumor or tumor microenvironment itself. Supportive of this is an almost general expression of IL-6/s-IL-6R in tumor cells and IL-6 in vasculature in the tumor microenvironment. Other studied cytokines/receptors were remarkably stable across all measurements.
Assuntos
Carcinoma de Células Renais/sangue , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Interleucina-6/sangue , Neoplasias Renais/sangue , Veias Renais/metabolismo , Idoso , Carcinoma de Células Renais/metabolismo , Citocinas/sangue , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Citocinas/sangue , Microambiente Tumoral/fisiologiaRESUMO
OBJECTIVE: Endothelial disturbance is well known as one of the causes of thrombosis. This study measured von Willebrand factor (vWF) and soluble thrombomodulin (sTM) in renal vein blood to evaluate for the risk of thrombosis after kidney transplantation. METHODS: A cross-sectional study that included 61 consecutive recipients of kidney transplant. The sTM and activity of vWF were evaluated in blood of the renal vein at the time of reperfusion. RESULTS: The renal vein blood had higher values of vWF activity and sTM concentration than the peripheral blood. In the first minutes of reperfusion, the concentration of thrombomodulin was the highest but activity of vWF was the lowest. As the reperfusion continued, thrombomodulin gradually decreased, but vWF increased. The strong correlations of TMs and vWF with warm ischemia were observed (r = 0.5577 and r = 0.3429, respectively). Thrombosis was found in about 10% of all recipients. However, other complications, such as delayed graft function or ureter necrosis, were associated with high values of vWF and sTM. They were correlated with increased sTM concentration and activity of vWF (P < .006 and P < .05, respectively). This was confirmed by analysis of the receiver operator characteristic curve. The area under the curve values for TMs and vWF were 0.762 and 0.602, respectively (P < .0001 and P < .015, respectively). The cutoff points for sTM and vWF were 14.89 ng/mL and 129.89%, respectively. Positive prediction value sTM and vWF were 76% and 66% and negative prediction value 69% and 59%, respectively. CONCLUSIONS: The endothelium of a transplanted kidney could be involved in the pathogenesis of renal thrombosis. Endothelial protection during harvesting can greatly contribute to the improvement of transplantation outcomes. The renal pool of sTM and vWF could be a useful marker of the risk of renal thrombosis.
Assuntos
Nefropatias/etiologia , Complicações Pós-Operatórias/etiologia , Trombomodulina/análise , Trombose/etiologia , Fator de von Willebrand/análise , Adulto , Biomarcadores/sangue , Estudos Transversais , Endotélio Vascular/metabolismo , Feminino , Humanos , Rim/irrigação sanguínea , Nefropatias/sangue , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Período Pré-Operatório , Veias Renais/metabolismo , Medição de Risco , Fatores de Risco , Trombose/sangueRESUMO
OBJECTIVE: Tissue factor (TF) is a membrane component of many cells and a strong activator of blood coagulation. Damage to the cells induces an increase in its expression and concentration in blood plasma. The injury and breakdown of the cells is inseparably connected with the harvesting and preservation of the kidney. PURPOSE: The aim of the study was an analysis of TF in the renal vein after of restoration of circulation in the transplanted kidney. An additional goal was to investigate the impact of warm ischemia on TF. MATERIALS AND METHODS: The examined group included 61 kidney recipients. Blood was taken from the renal vein in the first minute during reperfusion. Simultaneously, blood from a peripheral vein was also drawn. Apart from tissue factor (TF), I also examined thrombin/antithrombin complexes and fragments 1+2 of prothrombin. RESULTS: In blood from renal veins, I noticed higher level of TF, thrombin/antithrombin complexes and fragments 1+2 of prothrombin in comparison with blood from peripheral veins (P < .0048, P < .016, P < .046, respectively). The 29 recipients (47% of the total) with postoperative complications had much higher concentrations of TF than others (P < .019). TF showed a strong positive correlation with the time of warm ischemia (r = 0.53864, P < .05). CONCLUSIONS: The donor kidney appeared to be one of the main sources of TF in the blood of recipients. Warm ischemia significantly increased its concentration in renal vein blood. This concentration of TF may be associated with damage to the kidney. TF significantly increased the risk of postoperative complications.
Assuntos
Transplante de Rim/efeitos adversos , Rim/irrigação sanguínea , Complicações Pós-Operatórias/etiologia , Tromboplastina/análise , Transplantes/irrigação sanguínea , Isquemia Quente/efeitos adversos , Adulto , Antitrombina III , Coagulação Sanguínea , Feminino , Humanos , Masculino , Peptídeo Hidrolases/sangue , Protrombina/metabolismo , Veias Renais/metabolismo , Fatores de RiscoRESUMO
Idiopathic varicocele is closely associated with male infertility or subfertility. Sertoli cell is a very important regulator of spermatogenesis. We investigated the morphofunctional alterations in the Sertoli cell and its possible involvement in the establishment of testicular primary lesion in experimental left-sided varicocele, induced from peripuberty. Twenty-five male peripubertal rats (44 days postpartum [dpp]) were distributed into two groups: control (C) and varicocele (V). Experimental left varicocele was induced in rats through the partial ligature of the left renal vein. Euthanasia was performed at 100 dpp. Testicular histopathology and testosterone plasmatic level were evaluated. Transferrin and vimentin proteins were, respectively, used as immunomarkers of Sertoli cell function and structure. Significant reductions in vimentin and transferrin expressions were noticed in androgen-dependent stages (VII and VIII) of the seminiferous epithelium cycle in V rats; testosterone plasmatic level was also reduced. Bilateral testicular histopathological alterations were found in V rats, mainly massive germ cell desquamation. The histological damage and changes in protein expressions occurred bilaterally. The relevant impairment of the functional and structural characteristics of the Sertoli cell, together with the typical massive germ cell desquamation, indicates that Sertoli cell changes can primarily contribute to the significant testicular dysfunction associated with varicocele.
Assuntos
Infertilidade Masculina/etiologia , Células de Sertoli/metabolismo , Espermatogênese/efeitos dos fármacos , Varicocele/etiologia , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Células Germinativas/metabolismo , Heparina/farmacologia , Ligadura , Masculino , Prognóstico , Ratos , Ratos Wistar , Veias Renais/metabolismo , Testículo/metabolismo , Testosterona/farmacologia , Transferrina/genética , Transferrina/metabolismo , Vimentina/genética , Vimentina/metabolismoRESUMO
The kidney vasculature has a unique and complex architecture that is central for the kidney to exert its multiple and essential physiological functions with the ultimate goal of maintaining homeostasis. An appropriate development and coordinated assembly of the different vascular cell types and their association with the corresponding nephrons is crucial for the generation of a functioning kidney. In this review we provide an overview of the renal vascular anatomy, histology, and current knowledge of the embryological origin and molecular pathways involved in its development. Understanding the cellular and molecular mechanisms involved in renal vascular development is the first step to advance the field of regenerative medicine.
Assuntos
Rim/irrigação sanguínea , Neovascularização Fisiológica/fisiologia , Néfrons/irrigação sanguínea , Artéria Renal/anatomia & histologia , Veias Renais/anatomia & histologia , Animais , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Rim/embriologia , Rim/metabolismo , Neovascularização Fisiológica/genética , Néfrons/embriologia , Néfrons/metabolismo , Medicina Regenerativa/métodos , Medicina Regenerativa/tendências , Artéria Renal/embriologia , Artéria Renal/metabolismo , Veias Renais/embriologia , Veias Renais/metabolismoRESUMO
The kidney vasculature facilitates the excretion of wastes, the dissemination of hormones, and the regulation of blood chemistry. To carry out these diverse functions, the vasculature is regionalized within the kidney and along the nephron. However, when and how endothelial regionalization occurs remains unknown. Here, we examine the developing kidney vasculature to assess its 3-dimensional structure and transcriptional heterogeneity. First, we observe that endothelial cells (ECs) grow coordinately with the kidney bud as early as E10.5, and begin to show signs of specification by E13.5 when the first arteries can be identified. We then focus on how ECs pattern and remodel with respect to the developing nephron and collecting duct epithelia. ECs circumscribe nephron progenitor populations at the distal tips of the ureteric bud (UB) tree and form stereotyped cruciform structures around each tip. Beginning at the renal vesicle (RV) stage, ECs form a continuous plexus around developing nephrons. The endothelial plexus envelops and elaborates with the maturing nephron, becoming preferentially enriched along the early distal tubule. Lastly, we perform transcriptional and immunofluorescent screens to characterize spatiotemporal heterogeneity in the kidney vasculature and identify novel regionally enriched genes. A better understanding of development of the kidney vasculature will help instruct engineering of properly vascularized ex vivo kidneys and evaluate diseased kidneys.
Assuntos
Embrião de Mamíferos/embriologia , Células Endoteliais/metabolismo , Túbulos Renais Distais/embriologia , Organogênese/fisiologia , Artéria Renal/embriologia , Veias Renais , Animais , Embrião de Mamíferos/citologia , Células Endoteliais/citologia , Células-Tronco Fetais/metabolismo , Imunofluorescência/métodos , Túbulos Renais Distais/citologia , Camundongos , Artéria Renal/citologia , Veias Renais/crescimento & desenvolvimento , Veias Renais/metabolismo , Transcrição Gênica/fisiologia , Uretra/citologia , Uretra/embriologiaRESUMO
Renal sympathetic activity affects blood pressure in part by increasing renovascular resistance via release of norepinephrine (NE) from sympathetic nerves onto renal arteries. Here we test the idea that adipose tissue adjacent to renal blood vessels, i.e. renal perivascular adipose tissue (RPVAT), contains a pool of NE which can be released to alter renal vascular function. RPVAT was obtained from around the main renal artery/vein of the male Sprague Dawley rats. Thoracic aortic PVAT and mesenteric PVAT also were studied as brown-like and white fat comparators respectively. RPVAT was identified as a mix of white and brown adipocytes, because of expression of both brown-like (e.g. uncoupling protein 1) and white adipogenic genes. All PVATs contained NE (ng/g tissue, RPVAT:524⯱â¯68, TAPVAT:740⯱â¯16, MPVAT:96⯱â¯24). NE was visualized specifically in RPVAT adipocytes by immunohistochemistry. The presence of RPVAT (+RPVAT) did not alter the response of isolated renal arteries to NE compared to responses of arteries without RPVAT (-RPVAT). By contrast, the maximum contraction to the sympathomimetic tyramine was ~2× greater in the renal artery +PVAT versus -PVAT. Tyramine-induced contraction in +RPVAT renal arteries was reduced by the α1-adrenoceptor antagonist prazosin and the NE transporter inhibitor nisoxetine. These results suggest that tyramine caused release of NE from RPVAT. Renal denervation significantly (>50%) reduced NE content of RPVAT but did not modify tyramine-induced contraction of +RPVAT renal arteries. Collectively, these data support the existence of a releasable pool of NE in RPVAT that is independent of renal sympathetic innervation and has the potential to change renal arterial function.
Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Norepinefrina/metabolismo , Comunicação Parácrina , Artéria Renal/metabolismo , Veias Renais/metabolismo , Vasoconstrição , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/inervação , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/inervação , Animais , Relação Dose-Resposta a Droga , Masculino , Comunicação Parácrina/efeitos dos fármacos , Ratos Sprague-Dawley , Artéria Renal/efeitos dos fármacos , Artéria Renal/inervação , Veias Renais/inervação , Transdução de Sinais , Simpatectomia , Sistema Nervoso Simpático/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
Venous and arterial walls are responsive to sympathetic system and circulating substances, nevertheless, very few is known about the venous blood flow regulation simultaneously to arterial vascular beds. In this study, we compared the venous and arterial blood flow regulation in visceral and muscular beds upon injection of different doses of vasoactive drugs which act in arterial vascular beds. Anesthetized adult male Wistar rats underwent to right femoral artery and vein cannulation for hemodynamic recordings and infusion of drugs. Doppler flow probes were placed around the left renal artery and vein, and left femoral artery and vein to evaluate the changes in flood flow. Phenylephrine (PHE) injection (α1-adrenergic receptor agonist) elicited vasoconstriction in all arteries and veins. Intravenous prazosin (PZS) (1mg/kg, α1-adrenergic receptor blocker) caused renal artery vasodilation, but not in the other beds. Vasoconstrictor effect of PHE was abolished by PZS in all vascular beds, except in femoral vein. Phentolamine (PTL) injection (1mg/kg, α1/α2-adrenergic receptor blocker) produced renal artery vasodilation with no change in other beds. After PTL, the vasoconstriction evoked by PHE was abolished in all vascular beds. Sodium Nitroprusside (SNP), a nitric oxide donor, elicited vasodilation in all beds, and after PTL but not post PZS injection, SNP enhanced the vasodilatory effect in femoral vein. Our findings suggest that the vasoconstriction in renal and femoral veins is mediated by different subtypes of α-adrenoceptors. The nitric oxide-dependent vasodilation in femoral vein enhances when α2-adrenoceptors are not under stimulation, but not in the other vascular beds investigated.
Assuntos
Veia Femoral/metabolismo , Hemodinâmica , Óxido Nítrico/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Circulação Renal , Veias Renais/metabolismo , Adrenérgicos/administração & dosagem , Animais , Velocidade do Fluxo Sanguíneo , Veia Femoral/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Injeções Intravenosas , Masculino , Doadores de Óxido Nítrico/administração & dosagem , Ratos Wistar , Receptores Adrenérgicos alfa/efeitos dos fármacos , Fluxo Sanguíneo Regional , Circulação Renal/efeitos dos fármacos , Veias Renais/efeitos dos fármacos , Transdução de Sinais , Vasoconstrição , Vasoconstritores/administração & dosagem , Vasodilatação , Vasodilatadores/administração & dosagemRESUMO
PURPOSE OF REVIEW: Renal arteriovenous oxygen shunting has been proposed as a mechanism by which oxygen supplied to the kidney can bypass the renal parenchyma. Shunting could, therefore, play a crucial role in renal hypoxia and hyperoxia. In the absence of suitable quantitative experimental methods, computational modeling has been employed in recent years to estimate the extent and potential impact of oxygen shunting. RECENT FINDINGS: Overestimation of the separation distance between arteries and veins was suggested to be responsible for previous findings that only negligible amounts of oxygen are shunted in the preglomerular vasculature. However, models considering the correct separation distance and wrapping of artery-vein pairs still showed shunting at negligible levels of less than 1% of total renal oxygen delivery. The effect of reverse CO2 shunting on the oxygen-hemoglobin dissociation curve was found to impair, rather than promote, preglomerular oxygen shunting. SUMMARY: Oxygen is unlikely to be shunted along the preglomerular vasculature in sufficient quantities to affect renal oxygenation. There may be substantial shunting at the level of the postglomerular vasculature, but more extensive efforts in structural imaging and computational modeling are needed to quantify it reliably.
Assuntos
Hipóxia/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Consumo de Oxigênio/fisiologia , Oxigênio/metabolismo , Circulação Renal/fisiologia , Dióxido de Carbono/metabolismo , Humanos , Hipóxia/fisiopatologia , Rim/irrigação sanguínea , Rim/fisiologia , Nefropatias/fisiopatologia , Glomérulos Renais/metabolismo , Glomérulos Renais/fisiologia , Glomérulos Renais/fisiopatologia , Artéria Renal/metabolismo , Veias Renais/metabolismoRESUMO
Plasma levels of several amino acids are correlated with metabolic dysregulation in obesity and type 2 diabetes. To increase our understanding of human amino-acid metabolism, we aimed to determine splanchnic interorgan amino-acid handling. Twenty patients planned to undergo a pylorus preserving pancreatico-duodenectomy were included in this study. Blood was sampled from the portal vein, hepatic vein, superior mesenteric vein, inferior mesenteric vein, splenic vein, renal vein, and the radial artery during surgery. The difference between arterial and venous concentrations of 21 amino acids was determined using liquid chromatography as a measure of amino-acid metabolism across a given organ. Whereas glutamine was significantly taken up by the small intestine (121.0 ± 23.8 µmol/L; P < 0.0001), citrulline was released (-36.1 ± 4.6 µmol/L; P < 0.0001). This, however, was not seen for the colon. Interestingly, the liver showed a small, but a significant uptake of citrulline from the circulation (4.8 ± 1.6 µmol/L; P = 0.0138) next to many other amino acids. The kidneys showed a marked release of serine and alanine into the circulation (-58.0 ± 4.4 µmol/L and -61.8 ± 5.2 µmol/L, P < 0.0001), and a smaller, but statistically significant release of tyrosine (-12.0 ± 1.3 µmol/L, P < 0.0001). The spleen only released taurine (-9.6 ± 3.3 µmol/L; P = 0.0078). Simultaneous blood sampling in different veins provides unique qualitative and quantitative information on integrative amino-acid physiology, and reveals that the well-known intestinal glutamine-citrulline pathway appears to be functional in the small intestine but not in the colon.
Assuntos
Aminoácidos/sangue , Neoplasias Duodenais/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreaticoduodenectomia/métodos , Circulação Esplâncnica/fisiologia , Idoso , Colo/irrigação sanguínea , Colo/metabolismo , Neoplasias Duodenais/irrigação sanguínea , Neoplasias Duodenais/cirurgia , Feminino , Veias Hepáticas/metabolismo , Humanos , Intestino Delgado/irrigação sanguínea , Intestino Delgado/metabolismo , Rim/irrigação sanguínea , Rim/metabolismo , Fígado/irrigação sanguínea , Fígado/metabolismo , Masculino , Veias Mesentéricas/metabolismo , Pessoa de Meia-Idade , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/cirurgia , Veia Porta/metabolismo , Artéria Radial/metabolismo , Veias Renais/metabolismo , Baço/irrigação sanguínea , Baço/metabolismo , Veia Esplênica/metabolismoRESUMO
OBJECTIVES: The aim of this study was to identify new predictors of kidney graft primary dysfunction from results of metabolic, electrolyte composition, and preservation solution effluent osmolality analyses of kidneys from deceased donors. MATERIALS AND METHODS: Samples of left renal veins in Custodiol preservation solution (produced by Dr. F. Kohler, Chemie, Bensheim, Germany) from kidney explants and from back table surgical procedures were obtained from 55 deceased donors. We compared metabolic parameters (glucose and lactate levels), electrolyte composition (potassium, sodium, calcium, chlorine), and effluent osmolality of kidney samples from donors whose recipients had satisfactory initial graft function (n = 44) and dysfunction (n = 22). Values are shown as median and interquartile ranges between the 25th and 75th percentiles. We used the Mann-Whitney U test to compare quantitative variables. RESULTS: Statistically significant differences were observed in effluent osmolality results between kidneys that resulted in satisfactory graft function (median, 85; interquartile range, 65.5-97.1) and those that did not result in satisfactory graft function (median, 103.25; interquartile range, 78.7-125.75) (P = .045). We also observed a trend toward significance in sodium ion levels (P = .073) and lactate levels (P = .09). No statistically significant differences were shown in samples obtained from the back table surgical procedure. CONCLUSIONS: As a predictor of an initially satisfactory functioning deceased-donor kidney graft, it is possible to use the level of osmolality in Custodiol solution effluent obtained at explant.
Assuntos
Transplante de Rim/efeitos adversos , Soluções para Preservação de Órgãos/efeitos adversos , Disfunção Primária do Enxerto/etiologia , Veias Renais/efeitos dos fármacos , Preservação de Tecido/métodos , Adulto , Morte Encefálica , Feminino , Glucose/efeitos adversos , Glucose/química , Humanos , Masculino , Manitol/efeitos adversos , Manitol/química , Pessoa de Meia-Idade , Nefrectomia , Soluções para Preservação de Órgãos/química , Soluções para Preservação de Órgãos/metabolismo , Concentração Osmolar , Cloreto de Potássio/efeitos adversos , Cloreto de Potássio/química , Disfunção Primária do Enxerto/diagnóstico , Procaína/efeitos adversos , Procaína/química , Veias Renais/metabolismo , Fatores de Risco , Doadores de TecidosRESUMO
BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL or LCN2) is an iron-transporting factor which possesses various activities such as amelioration of kidney injury and host defense against pathogens. Its circulating concentrations are elevated in acute and chronic kidney diseases and show a positive correlation with poor renal outcome and mortality, but its clinical significance in maintenance hemodialysis (HD) patients remains elusive. METHODS: Serum NGAL levels were determined by enzyme-linked immunosorbent assay in out-patient, Japanese HD subjects. Their correlation to laboratory findings and morbidity (as development of severe infection or serum albumin reduction) was investigated using linear regression analysis and χ2 test. RESULTS: Pre-dialysis serum NGAL levels in HD patients were elevated by 13-fold compared to healthy subjects (n=8, P<0.001). In a cross-sectional study of 139 cases, serum NGAL concentrations were determined independently by % creatinine generation rate (an indicator of muscle mass, standardized coefficient ß=0.40, P<0.001), peripheral blood neutrophil count (ß=0.38, P<0.001) and anion gap (which likely reflects dietary protein intake, ß=0.16, P<0.05). Iron administration to anemic HD patients caused marked elevation of peripheral blood hemoglobin, serum ferritin and iron-regulatory hormone hepcidin-25 levels, but NGAL levels were not affected. In a prospective study of 87 cases, increase in serum albumin levels a year later was positively associated to baseline NGAL levels by univariate analysis (r=0.36, P<0.01). Furthermore, within a year, patients with the lowest NGAL tertile showed significantly increased risk for marked decline in serum albumin levels (≥0.4 g/dl; odds ratio 5.5, 95% confidence interval 1.5-20.3, P<0.05) and tendency of increased occurrence of severe infection requiring admission (odds ratio 3.1, not significant) compared to the middle and highest tertiles. CONCLUSION: Low serum NGAL levels appear to be associated with current malnutrition and also its progressive worsening in maintenance HD patients.
Assuntos
Lipocalinas/sangue , Desnutrição/sangue , Proteínas Proto-Oncogênicas/sangue , Diálise Renal , Proteínas de Fase Aguda , Fatores Etários , Idoso , Aorta/metabolismo , Biomarcadores/sangue , Progressão da Doença , Feminino , Seguimentos , Humanos , Inflamação/patologia , Ferro/administração & dosagem , Ferro/farmacologia , Modelos Lineares , Lipocalina-2 , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Veias Renais/metabolismo , Albumina Sérica/metabolismoRESUMO
BACKGROUND: MicroRNAs (miRs) are small non-coding RNAs that are important regulators of gene expression and have been implicated in atherosclerosis. Kidney injury distal to atherosclerotic renal artery stenosis (ARAS) is aggravated by atherosclerosis. Therefore, this study tested the hypothesis that renal miR expression would be altered in patients with ARAS. METHODS: Patients with essential hypertension (EH; n = 13) or ARAS (n = 13) underwent a 3-day protocol study under controlled conditions. For miR levels, blood samples were collected from EH and ARAS renal vein (RV) and inferior vena cava or peripheral vein of matched normotensive healthy volunteers (HV; n = 13) and patients with coronary atherosclerosis (CA; n = 11). Single-renal blood flow was measured in EH and ARAS using computer tomography to calculate renal gradients and release of miRs. RESULTS: Glomerular filtration rate (GFR) was lower in ARAS compared with the other groups. Systemic levels of most miRs were elevated in CA. RV miR levels were lower than systemic levels in both ARAS and EH. GFR-adjusted RV levels of miR-21, 155 and 210 were reduced only in ARAS patients compared with systemic levels in HV, although cross-kidney gradients were not different from EH. RV levels of miR-21, 126, 155 and 210 correlated with GFR. CONCLUSIONS: Levels of atherosclerosis-related miR-21, 126, 155 and 210 are decreased in the stenotic-kidney vein of ARAS compared with EH patients, likely due to decreased GFR. Yet, these miRs might be implicated in modulating renal injury in ARAS, and their RV level may be a marker reflecting their renal expression.
Assuntos
Aterosclerose/diagnóstico , Biomarcadores/sangue , Hipertensão/diagnóstico , MicroRNAs/genética , Obstrução da Artéria Renal/diagnóstico , Veias Renais/metabolismo , Idoso , Aterosclerose/sangue , Aterosclerose/genética , Estudos de Casos e Controles , Citocinas/sangue , Hipertensão Essencial , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão/sangue , Hipertensão/genética , Masculino , MicroRNAs/sangue , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Obstrução da Artéria Renal/sangue , Obstrução da Artéria Renal/genética , Circulação Renal , Veias Renais/patologiaRESUMO
The renal vasculature, like all vessels, is lined by a thin layer of simple squamous epithelial cells called an endothelium. These endothelial-lined vessels can be subdivided into four major compartments: arteries, veins, capillaries and lymphatics. The renal vasculature is a highly integrated network that forms through the active processes of angiogenesis and vasculogenesis. Determination of the precise contribution of these two processes and of the molecular signaling that governs the differentiation, specification and maturation of these critical cell populations is the focus of an actively evolving field of research. Although much of the focus has concentrated on the origin of the glomerular capillaries, in this review we extend the investigation to the origins of the endothelial cells throughout the entire kidney and the signaling events that cause their distinct functional and molecular profiles. A thorough understanding of endothelial cell biology may play a critical role in a better understanding of renal vascular diseases.
Assuntos
Capilares/fisiologia , Linhagem da Célula , Células Endoteliais/fisiologia , Endotélio Vascular/fisiologia , Rim/irrigação sanguínea , Artéria Renal/fisiologia , Veias Renais/fisiologia , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Capilares/citologia , Capilares/metabolismo , Células Endoteliais/metabolismo , Endotélio Linfático/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Nefropatias/fisiopatologia , Neovascularização Fisiológica , Organogênese , Artéria Renal/citologia , Artéria Renal/metabolismo , Veias Renais/citologia , Veias Renais/metabolismo , Transdução de SinaisRESUMO
MicroRNA-26a (miR-26a) is a post-transcriptional regulator that inhibits cellular differentiation and apoptosis. Renal vascular disease (RVD) induces ischemic injury characterized by tubular cell apoptosis and interstitial fibrosis. We hypothesized that miR-26a levels are reduced in the poststenotic kidney and that kidney repair achieved by adipose tissue-derived mesenchymal stem cells (ad-MSCs) is associated with restored miR-26a levels. Renal function and renal miR-26a levels were assessed in pigs with RVD not treated (n=7) or 4 weeks after intrarenal infusion of ad-MSC (2.5×10(5) cells/kg; n=6), patients with RVD (n=12) or essential hypertension (n=12), and healthy volunteers (n=12). In addition, the direct effect of miR-26a on apoptosis was evaluated in a renal tubular cell culture. Compared with healthy control kidneys, swine and human poststenotic kidneys had 45.5±4.3% and 90.0±3.5% lower levels of miR-26a, respectively, which in pigs, localized to the proximal tubules. In pigs, ad-MSC delivery restored tubular miR-26a expression, attenuated tubular apoptosis and interstitial fibrosis, and improved renal function and tubular oxygen-dependent function. In vitro, miR-26a inhibition induced proximal tubular cell apoptosis and upregulated proapoptotic protein expression, which were both rescued by ad-MSC. In conclusion, decreased tubular miR-26a expression in the poststenotic kidney may be responsible for tubular cell apoptosis and renal dysfunction but can be restored using ad-MSC. Therefore, miR-26a might be a novel therapeutic target in renovascular disease.
Assuntos
Injúria Renal Aguda/sangue , Transplante de Células-Tronco Mesenquimais/métodos , MicroRNAs/sangue , Obstrução da Artéria Renal/sangue , Veias Renais/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/terapia , Idoso , Análise de Variância , Animais , Biópsia por Agulha , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Testes de Função Renal , Masculino , Valores de Referência , Obstrução da Artéria Renal/patologia , Obstrução da Artéria Renal/terapia , Índice de Gravidade de Doença , Suínos , Resultado do TratamentoRESUMO
Renovascular hypertension is a syndrome which encompasses the physiological response of the kidney to changes in renal blood flow and renal perfusion pressure. Such physiological changes can occur with renal artery occlusion irrespective of the severity of the lesion. We have analyzed hypertensive patients with mild renal artery stenosis and compared them to patients with no stenosis. Renal vein renin sampling from catheterization of the renal vein was performed in all these patients. Patients with mild stenosis had higher renal vein renin ratio (3.01 ± 1.5) than the patients with no stenosis (1.10 ± 0.29; p = 0.002). Patients with mild stenosis were also found to have higher diastolic blood pressure and renal artery resistive indices when compared to patients with no stenosis. We therefore conclude that mild stenosis can precipitate renin-mediated hypertension in renovascular stenosis and also emphasis that parameters pertinent to renal physiology need to be evaluated before considering treatment options in patients with renal artery stenosis and medical management with RAAS blockade is the preferred modality of therapy for patients with renin-mediated hypertension.
Assuntos
Hipertensão Renovascular/etiologia , Rim/fisiopatologia , Obstrução da Artéria Renal/complicações , Renina/sangue , Idoso , Angiografia , Pressão Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Veias Renais/metabolismo , Estudos Retrospectivos , Ultrassonografia Doppler DuplaRESUMO
Endothelial progenitor cells (EPCs) participate in renal repair, but their number and function may be impaired by exposure to cardiovascular risk factors. The number of circulating EPCs is decreased in essential and renovascular hypertensive patients, but the effects of hypertension on EPC function are incompletely understood. We hypothesized that EPC function was preserved under well-controlled conditions in treated hypertensive patients. Patients with atherosclerotic renal artery stenosis (ARAS; n=22) or essential hypertension (n=24) were studied during controlled sodium intake and antihypertensive regimen. Late-outgrowth EPCs were isolated from the inferior vena cava (IVC) and renal vein blood of ARAS and essential hypertension patients and a peripheral vein of matched normotensive controls (n=18). The angiogenic function of EPCs was assessed in vitro, and multidetector computed tomography was used to measure single-kidney hemodynamics and function in ARAS and essential hypertension patients. Inflammatory biomarkers and EPC homing signal levels and renal release were calculated. Inferior vena cava and renal vein-obtained EPC function were similar in ARAS and essential hypertension patients and comparable to that in normal controls (tube length, 171.86±16.846, 191.09±14.222, 174.925±19.774 µm, respectively). Function of renal vein-obtained EPCs directly correlated with stenotic kidney glomerular filtration rate, EPC homing factors, and anti-inflammatory mediator levels in ARAS patients. Therefore, EPC function was relatively preserved in ARAS patients, although it directly correlated with renal function. Adequate EPC function supports the feasibility of using autologous EPCs as a therapeutic option in essential and renovascular hypertensive patients. Homing signals and inflammatory mediators may potentially regulate EPC angiogenic function.
Assuntos
Anti-Hipertensivos/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Células-Tronco/efeitos dos fármacos , Aterosclerose/sangue , Aterosclerose/fisiopatologia , Biomarcadores/sangue , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Taxa de Filtração Glomerular , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Hipertensão Renovascular/sangue , Hipertensão Renovascular/fisiopatologia , Mediadores da Inflamação/sangue , Rim/irrigação sanguínea , Rim/fisiopatologia , Estudos Prospectivos , Obstrução da Artéria Renal/sangue , Obstrução da Artéria Renal/fisiopatologia , Circulação Renal , Veias Renais/metabolismo , Veias Renais/patologia , Células-Tronco/metabolismo , Células-Tronco/patologia , Veia Cava Inferior/metabolismo , Veia Cava Inferior/patologiaRESUMO
The purpose of this study was to investigate the biochemical, histopathological and immunohistochemical effects of venous blood on ischemia/reperfusion-induced oxidative DNA damage and mutation in rabbit kidneys in comparison to melatonin treatment, which has a known protective effect against ischemia/reperfusion (IR) injury. The rabbits were divided into five groups: renal ischemia (RI), renal ischemia-reperfusion (RIR), renal ischemia-venous blood-reperfusion (RIVR), melatonin + renal ischemia-reperfusion (MRIR), and the healthy sham control group (HG). Melatonin (2.5 mg/kg delivered intraperitoneally) was administered one hour prior to ischemia. In the RIVR group, 1 ml of venous blood was administered 5 minutes before the reperfusion. The xanthine oxidase activity in the kidney tissue was determined as 53.50 ± 1.72, 31.00 ± 6.39, 45.66 ± 9.20, 28.66 ± 6.05 and 14.33 ± 1.28 U/g protein; the MDA levels were 6.32 ± 0.02, 19.50 ± 1.33, 7.00 ± 0.96, 7.50 ± 0.76 and 4.75 ± 0.34 mmol/g protein; and the GSH levels were 4.50 ± 1.08, 2.76 ± 0.13, 5.48 ± 0.22, 4.93 ± 0.55 and 6.98 ± 0.33 nmol/g protein in the RI, RIR, RIVR, MRIR and HG groups, respectively. Blood, blood urea nitrogen (BUN) and creatinine levels were classified as high only in the RIR group. The MRIR and RIVR groups, in which oxidative stress was best suppressed, had much milder histopathological and immunohistochemical findings compared to the RIR group. This study has revealed that it is useful to initiate reperfusion of the ischemic tissue with venous blood.
Assuntos
Rim/metabolismo , Estresse Oxidativo , Veias Renais/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Imuno-Histoquímica , Rim/patologia , Rim/cirurgia , Masculino , Coelhos , Veias Renais/patologia , Veias Renais/cirurgia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/cirurgiaRESUMO
BACKGROUND: Patients with cirrhosis have substantial circulatory imbalance between vasoconstrictive and vasodilating forces. The study of circulatory vasoactive peptides may provide important pathophysiological information. This study aimed to assess concentrations, organ extraction and relations to haemodynamic changes in the pro-peptides copeptin, proadrenomedullin and pro-atrial natriuretic peptide (proANP) in patients with cirrhosis. MATERIALS AND METHODS: Fifty-four cirrhotic patients and 15 controls were characterized haemodynamically during a liver vein catheterization. Copeptin, proadrenomedullin and proANP were measured in hepatic and renal veins and the femoral artery. RESULTS: We found no differences in concentrations of copeptin and proadrenomedullin between patients and controls. ProANPs were higher in cirrhotic patients, median 138 pm (25/75 percentiles 101-194) compared with controls, median 91 pm (25/75 percentiles 82-153) P=0·02. ProANPs were higher in the femoral artery and renal vein, median 140 pm and 116 pm (25/75 percentiles 109-191 and 92-164, respectively), compared with controls, median 99 and 81 (25/75 percentiles 85-146 and 66-123) P=0·02 and P=0·007, respectively. We found no extraction of copeptin, proadrenomedullin or proANP over the liver. Copeptin correlated with portal pressure (R=0·50, P<0·001). Proadrenomedullin correlated with portal pressure (R=0·48, P<0·001) and heart rate (R=0·36, P<0·01). ProANP correlated with cardiac output (R=0·46, P<0·002) and portal pressure (R=0·32, P<0·02). All propeptides correlated with Child score (R>0·31, P<0·03). CONCLUSIONS: Pro-atrial natriuretic peptide is elevated in cirrhosis. Copeptin, proadrenomedullin and proANP are related to portal pressure and seem associated with systemic haemodynamics. These propeptides may participate in development and perpetuation of vasodilatation and hyperdynamic circulation in cirrhosis.
Assuntos
Adrenomedulina/metabolismo , Fator Natriurético Atrial/metabolismo , Glicopeptídeos/metabolismo , Cirrose Hepática/metabolismo , Precursores de Proteínas/metabolismo , Análise de Variância , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Feminino , Artéria Femoral/metabolismo , Veias Hepáticas/metabolismo , Humanos , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Veias Renais/metabolismo , Vasodilatação/fisiologiaRESUMO
AIMS: The mechanisms mediating kidney injury and repair in humans with atherosclerotic renal artery stenosis (ARAS) remain poorly understood. We hypothesized that the stenotic kidney releases inflammatory mediators and recruits progenitor cells to promote regeneration. METHODS AND RESULTS: Essential hypertensive (EH) and ARAS patients (n=24 each) were studied during controlled sodium intake and antihypertensive treatment. Inferior vena cava (IVC) and renal vein (RV) levels of CD34+/KDR+ progenitor cells, cell adhesion molecules, inflammatory biomarkers, progenitor cell homing signals, and pro-angiogenic factors were measured in EH and ARAS, and their gradient and net release compared with systemic levels in matched normotensive controls (n= 24). Blood pressure in ARAS was similar to EH, but the glomerular filtration rate was lower. Renal vein levels of soluble E-Selectin, vascular cell adhesion molecule-1, and several inflammatory markers were higher in the stenotic kidney RV vs. normal and EH RV (P < 0.05), and their net release increased. Similarly, stem-cell homing factor levels increased in the stenotic kidney RV. Systemic CD34+/KDR+ progenitor cell levels were lower in both EH and ARAS and correlated with cytokine levels. Moreover, CD34+/KDR+ progenitor cells developed a negative gradient across the ARAS kidney, suggesting progenitor cell retention. The non-stenotic kidney also showed signs of inflammatory processes, which were more subtle than in the stenotic kidney. CONCLUSION: Renal vein blood from post-stenotic human kidneys has multiple markers reflecting active inflammation that portends kidney injury and reduced function. CD34+/KDR+ progenitor cells sequestered within these kidneys may participate in reparative processes. These inflammation-related pathways and limited circulating progenitor cells may serve as novel therapeutic targets to repair the stenotic kidney.