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AIM: This study aimed to establish a prediction model in peritoneal dialysis patients to estimate the risk of technique failure and guide clinical practice. METHODS: Clinical and laboratory data of 424 adult peritoneal dialysis patients were retrospectively collected. The risk prediction models were built using univariate Cox regression, best subsets approach and LASSO Cox regression. Final nomogram was constructed based on the best model selected by the area under the curve. RESULTS: After comparing three models, the nomogram was built using the LASSO Cox regression model. This model included variables consisting of hypertension and peritonitis, serum creatinine, low-density lipoprotein, fibrinogen and thrombin time, and low red blood cell count, serum albumin, triglyceride and prothrombin activity. The predictive model constructed performed well using receiver operating characteristic curve and area under the curve value, C-index and calibration curve. CONCLUSION: This study developed and verified a new prediction instrument for the risk of technique failure among peritoneal dialysis patients.
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Nomogramas , Diálise Peritoneal , Humanos , Diálise Peritoneal/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco/métodos , Falha de Tratamento , Fatores de Risco , Idoso , Adulto , Falência Renal Crônica/terapia , Falência Renal Crônica/sangue , Valor Preditivo dos Testes , Curva ROCRESUMO
OBJECTIVE: To explore the diagnostic performance of diffusion kurtosis imaging (DKI) and incoherent intravoxel movement (IVIM) in evaluating the clinical and pathological characteristics in chronic kidney disease (CKD) compared to conventional diffusion-weighted imaging (DWI). METHODS: Forty-nine CKD patients and 24 healthy volunteers were included in this retrospective study from September 2020 to September 2021. All participants underwent MRI examinations before percutaneous renal biopsy. Coronal T2WI, axial T1WI and T2WI, and DWI (including IVIM and DKI) sequences obtained in one scan. We measured the apparent diffusion coefficient (ADC), true diffusion coefficient (Dt), pseudo-diffusion coefficient (Dp), perfusion fraction (fp), mean kurtosis (MK), and mean diffusivity (MD) values. One-way analysis of variance, correlation analysis, and receiver operating characteristic curve analysis were used in our study. RESULTS: Cortex and medulla ADC, MK, Dt, fp were significantly different between the healthy volunteers and CKD stages 1-2 (all p < 0.05). All diffusion parameters showed significant differences between CKD stages 1-2 and CKD stages 3-5 (all p < 0.05). Except for the uncorrelation between MDMedulla and vascular lesion score, all other diffusion parameters were low-to-moderately related to clinical and pathological indicators. fpMedulla was the best parameter to differentiate healthy volunteers from CKD stages 1-2. MKCortex was the best parameter to differentiate CKD stages 1-2 from that CKD stages 3-5. CONCLUSION: Renal cortex and medulla fp, Dt, and MK can provide more valuable information than ADC values for the evaluation of clinical and pathological characteristics of CKD patients, and thus can provide auxiliary diagnosis for fibrosis assessment and clinical management of CKD patients. ADVANCES IN KNOWLEDGE: IVIM and DKI can provide more diagnostic valuable information for CKD patients than conventional DWI.
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Imagem de Difusão por Ressonância Magnética , Insuficiência Renal Crônica , Humanos , Estudos Retrospectivos , Imagem de Difusão por Ressonância Magnética/métodos , Imagem de Tensor de Difusão/métodos , Movimento (Física) , Insuficiência Renal Crônica/diagnóstico por imagemRESUMO
BACKGROUND: Some patients with COVID-19 pneumonia also present with kidney injury, and autopsy findings of patients who died from the illness sometimes show renal damage. However, little is known about the clinical characteristics of kidney-related complications, including hematuria, proteinuria, and AKI. METHODS: In this retrospective, single-center study in China, we analyzed data from electronic medical records of 333 hospitalized patients with COVID-19 pneumonia, including information about clinical, laboratory, radiologic, and other characteristics, as well as information about renal outcomes. RESULTS: We found that 251 of the 333 patients (75.4%) had abnormal urine dipstick tests or AKI. Of 198 patients with renal involvement for the median duration of 12 days, 118 (59.6%) experienced remission of pneumonia during this period, and 111 of 162 (68.5%) patients experienced remission of proteinuria. Among 35 patients who developed AKI (with AKI identified by criteria expanded somewhat beyond the 2012 Kidney Disease: Improving Global Outcomes definition), 16 (45.7%) experienced complete recovery of kidney function. We suspect that most AKI cases were intrinsic AKI. Patients with renal involvement had higher overall mortality compared with those without renal involvement (28 of 251 [11.2%] versus one of 82 [1.2%], respectively). Stepwise multivariate binary logistic regression analyses showed that severity of pneumonia was the risk factor most commonly associated with lower odds of proteinuric or hematuric remission and recovery from AKI. CONCLUSIONS: Renal abnormalities occurred in the majority of patients with COVID-19 pneumonia. Although proteinuria, hematuria, and AKI often resolved in such patients within 3 weeks after the onset of symptoms, renal complications in COVID-19 were associated with higher mortality.
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Injúria Renal Aguda/etiologia , Betacoronavirus , Infecções por Coronavirus/complicações , Hematúria/etiologia , Pneumonia Viral/complicações , Proteinúria/etiologia , Adulto , Idoso , COVID-19 , Infecções por Coronavirus/mortalidade , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Prognóstico , Estudos Retrospectivos , SARS-CoV-2RESUMO
BACKGROUND: Putative endothelial progenitor cells (pEPCs) have been confirmed to participate in alleviation of renal fibrosis in several ischaemic diseases. However, their mechanistic effect on renal fibrosis, which is characterized by vascular regression and further rarefaction-related pathology, remains unknown. METHODS: To explore the effect and molecular mechanisms by which pEPCs act on unilateral ureteral obstruction (UUO)-induced renal fibrosis, we isolated pEPCs from murine bone marrow. In vivo, pEPCs (2 × 105 cells/day) and pEPC-MVs (microvesicles) were injected into UUO mice via the tail vein. In vitro, pEPCs were co-cultured with renal-derived pericytes. Pericyte-myofibroblast transition was evaluated using the myofibroblast marker α-smooth muscle actin (α-SMA) and pericyte marker platelet-derived growth factor receptor ß (PDGFR-ß). RESULTS: Exogenous supply of bone marrow-derived pEPCs attenuated renal fibrosis by decreasing pericyte-myofibroblast transition without significant vascular repair in the UUO model. Our results indicated that pEPCs regulated pericytes and their transition into myofibroblasts via pEPC-MVs. Co-culture of pericytes with pEPCs in vitro suggested that pEPCs inhibit transforming growth factor-ß (TGF-ß)-induced pericyte-myofibroblast transition via a paracrine pathway. CONCLUSION: pEPCs effectively attenuated UUO-induced renal fibrosis by inhibiting pericyte-myofibroblast transition via a paracrine pathway, without promoting vascular repair.
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Células da Medula Óssea , Células Progenitoras Endoteliais , Miofibroblastos , Comunicação Parácrina , Pericitos , Obstrução Ureteral , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Células Progenitoras Endoteliais/transplante , Fibrose , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/terapia , Masculino , Camundongos , Camundongos Transgênicos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Pericitos/metabolismo , Pericitos/patologia , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Obstrução Ureteral/terapiaRESUMO
BACKGROUND/AIMS: Free radical scavenger tempol is a protective antioxidant against ischemic injury. Tubular epithelial apoptosis is one of the main changes in the renal ischemia/reperfusion (I/R) injury. Meanwhile some proteins related with apoptosis and inflammation are also involved in renal I/R injury. We tested the hypothesis that tempol protects against renal I/R injury by activating protein kinase B/mammalian target of rapamycin (PKB, Akt/mTOR) and glycogen synthase kinase 3ß (GSK3ß) pathways as well as the coordinating apoptosis and inflammation related proteins. METHODS: The right renal pedicle of C57Bl/6 mouse was clamped for 30 minutes and the left kidney was removed in the study. The renal injury was assessed with serum parameters by an automatic chemistry analyzer. Renal expressions of Akt/mTOR and GSK3ß pathways were measured by western blot in I/R mice treated with saline or tempol (50mg/kg) and compared with sham-operated mice. RESULTS: The levels of blood urea nitrogen (BUN), creatinine and superoxide anion (O2.-) increased, and superoxide dismutase (SOD) and catalase (CAT) decreased significantly after renal I/R injury. However, tempol treatment prevented the changes. Besides, I/R injury reduced renal expression of p-Akt, p-GSK3ß, p-mTOR, Bcl2 and increased NF-κB, p-JNK and p53 in kidney, tempol significantly normalized these changes. In addition, renal I/R injury reduced the response of afferent arteriole to Angiotensin II (Ang II), while tempol treatment improved the activity of afferent arteriole. CONCLUSION: Tempol attenuates renal I/R injury. The protective mechanisms seem to relate with activation of PI3K/Akt/mTOR and GSK3ß pathways, inhibition of cellular damage markers and inflammation factors, as well as improvement of afferent arteriolar activity.
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Injúria Renal Aguda/tratamento farmacológico , Arteríolas/metabolismo , Óxidos N-Cíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Arteríolas/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Marcadores de Spin , Serina-Treonina Quinases TOR/metabolismoRESUMO
Residual renal function (RRF) is an important prognostic factor for peritoneal dialysis patients as it influences the quality of life and mortality. This study was conducted to explore the potential factors correlated with RRF. A cross-sectional study was conducted by recruiting 155 patients with residual GFR more than 1mL/min per 1.73m2 at the initiation of peritoneal dialysis. We collected the demographic characteristics, nutritional markers and biochemical parameters of all participants, and analyzed the correlation between these variables and residual GFR as well. The odds ratio of RRF loss associated with each of the nutritional markers and biochemical parameters were estimated by logistic regression model. The residual GFR was negatively correlated with serum phosphate (ORQ3 = 2.67, 95%CI: 1.03-6.92; ORQ4 = 3.45, 95%CI: 1.35-9.04), magnesium (ORQ4 = 3.77, 95%CI: 1.48-3.63), and creatinine (ORQ3 = 2.93, 95%CI: 1.09-7.88; ORQ4 = 8.64 95%CI: 2.79-26.78), while positively associated with normalized protein catabolic rate (ORQ3 = 0.24, 95%CI: 0.09-0.65; ORQ4 = 0.11, 95%CI: 0.03-0.35), 24 hours urine volume(ORQ1 = 22.87, 95%CI: 2.76-189.24; ORQ3 = 0.08, 95%CI: 0.02-0.28) and serum chlorine concentrations (ORQ1 = 5.34, 95%CI: 1.94-14.68; ORQ4 = 0.28, 95%CI: 0.09-0.85), respectively. Our study suggested that the nutritional markers and biochemical parameters, though not all, but at least in part were closely correlated with RRF in peritoneal dialysis patients.
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Taxa de Filtração Glomerular/fisiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/fisiopatologia , Rim/fisiopatologia , Diálise Peritoneal , Adulto , Creatinina/sangue , Estudos Transversais , Feminino , Humanos , Rim/patologia , Falência Renal Crônica/patologia , Falência Renal Crônica/terapia , Modelos Logísticos , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Razão de Chances , Diálise Peritoneal Ambulatorial Contínua , Fosfatos/sangue , Qualidade de VidaRESUMO
A 5/6 nephrectomized (Nx) rat model was employed to address the impact of telmisartan on CKD related renal injury and the underlying molecular mechanisms. It was noted that telmisartan provided protection for rats against 5/6 Nx induced lethality. Telmisartan treated 5/6 Nx rats manifested improved renal function as characterized by the higher GFR but lower urinary albumin, BUN and Scr as compared with that of control rats. Telmisartan treatment also significantly decreased systolic blood pressure and alleviated glomerulosclerosis and interstitial fibrosis. Mechanistic studies revealed that telmisartan possesses the capability to increase NO generation in the kidney. Further studies demonstrated that telmisartan promotes PPARγ expression, by which it specifically enhances nNOS expression in the kidneys after 5/6 Nx insult. Particularly, blockade of PPARγ signaling by GW9662 abolished the protective effect conferred by telmisartan, indicating that telmisartan induction of renal nNOS expression along with NO generation is dependent on PPARγ signaling. Together, our data support that telmisartan could be a promising drug for treatment of chronic kidney diseases in diverse clinical settings.
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Excess mesangial extracellular matrix (ECM) and mesangial cell proliferation is the major pathologic feature of diabetic nephropathy (DN). Fenofibrate, a PPARα agonist, has been shown to attenuate extracellular matrix formation in diabetic nephropathy. However, the mechanisms underlying this effect remain to be elucidated. In this study, the effect of fenofibrate on high-glucose induced cell proliferation and extracellular matrix exertion and its mechanisms were investigated in cultured rat mesangial cells by the methylthiazoletetrazolium (MTT) assay, flow cytometry and western blot. The results showed that treatment of mesangial cells (MCs) with fenofibrate repressed high-glucose induced up-regulation of extracellular matrix Collagen-IV, and inhibited entry of cell cycle into the S phase. This G1 arrest and ECM inhibition was caused by the reduction of phosphorylation and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT. On the contrary, PPARα siRNA accelerated high glucose-induced cell cycle progression by ERK1/2 and AKT activation. Taken together, fenofibrate ameliorated glucose-induced mesangial cell proliferation and matrix production via its inhibition of PI3K/AKT and ERK1/2 signaling pathways. Such mechanisms may contribute to the favorable effects of treatment using fenofibrate in diabetic nephropathy.
Assuntos
Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/enzimologia , Fenofibrato/farmacologia , Glucose/farmacologia , Células Mesangiais/citologia , Células Mesangiais/efeitos dos fármacos , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo IV/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Matriz Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células Mesangiais/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , PPAR alfa/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Regulação para Cima/efeitos dos fármacosRESUMO
Previous studies suggested that ß-blockers with adjunctive α1-blocking activities warrant renoprotective function other than the therapeutic effect on hypertension. The current report is designed to dissect the role of TJ0711, a novel ß-blocker with a 1:1 ratio for the ß1/α1 blocking activities, in renoprotection in SHR rats. It was noted that TJ0711 possesses similar potency for control of blood pressure as that of Carvedilol. However, TJ0711 is much more potent in terms of protecting SHR rats against hypertension induced renal injury. Specifically, SHR rats treated with 20mg/kg/day of TJ0711 manifested significantly lower levels for urine albumin and total protein. In line with these result, TJ0711 treated rats displayed much less severe pathological changes in the kidneys. Mechanistic studies revealed that TJ0711 improves kidney perfusion during the course of hypertensive insult by enhancing eNOS expression through suppressing inflammatory cytokine secretion. TJ0711 also attenuates Vasohibin-1 expression to prevent HIF-1α from signal-induced degradation, and by which it promotes HO-1 expression to protect SHR rats against oxidative stress induced by hypertension in the kidneys. Together, our data suggest that TJ0711 possesses higher potency for renoprotection while manifesting the similar effect on hypertension therapy as Carvedilol.
RESUMO
OBJECTIVES: This study aims to analyze the relationship between nutcracker syndrome (NCS) and nutcracker phenomenon (NCP) in glomerular nephritis (GN) of patients with symptom of isolated hematuria. Our observations reveal that patients with combined GN and NCP/NCS have dysmorphic urine red blood cells or mixed-morphological urine red blood cells while patients with NCS only (without GN) contain isomorphic urine red blood cells. PATIENTS AND METHODS: Clinical and pathological data of 32 patients with NCP and complicating GN were analyzed. A different group of 17 patients with NCS served as the control. All patients underwent color Doppler ultrasonography. Routine urine examination, red blood cell counts, and phase observations of urinary sediments were performed both before and after exercise. twenty four hour urinary protein and albumin quantities were determined. Twenty-nine patients underwent renal needle biopsy. RESULTS: All 32 patients were diagnosed with NCP. Results of urinary sediment examination of patients were either normal or showed isomorphic hematuria before exercise. Most patients exhibited mixed-morphological or dysmorphic hematuria at different degrees after exercise. Renal pathological findings in 29 patients included multiple types and showed no relevance to urinary examination results. All patients diagnosed with GN complicated by NCP were identified through clinical and laboratory examinations and renal biopsy. CONCLUSIONS: NCP may coexist with a glomerular disease. NCS patients with urine red blood cells of mixed morphology or showing dysmorphism after exercise should be noted, with or without the coexistence of GN. Renal needle biopsy must be performed when necessary to avoid adverse effects on the patient's condition.
Assuntos
Glomerulonefrite/complicações , Hematúria/etiologia , Glomérulos Renais/patologia , Síndrome do Quebra-Nozes/complicações , Adolescente , Adulto , Biópsia , Criança , Diagnóstico Diferencial , Feminino , Seguimentos , Glomerulonefrite/patologia , Hematúria/diagnóstico , Hematúria/urina , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Síndrome do Quebra-Nozes/diagnóstico , Estudos Retrospectivos , Ultrassonografia Doppler em Cores , Urinálise , Adulto JovemRESUMO
The safety of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) used in hemodialysis (HD) patients was evaluated. Medline, Embase, the Cochrane Library, some databases of clinical trial registries, grey literatures, other reference lists of eligible articles and review articles for the randomized clinical trials (RCTs) on comparison of ACEIs/ARBs or placebo in HD patients were retrieved. RCTs reporting the risk of hyperkalemia by using ACEIs/ARBs in HD patients were selected. Eight articles met the eligibility criteria and were subjected to meta-analysis by using the Cochrane Collaboration's RevMan 4.2 software package. The results showed that there was no significant difference in hyperkalemia in HD patients between ACEIs or ARBs group and control group (ACEIs vs. control: RD=0.03, 95% CI=-0.13-0.18, Z=0.34, P=0.73; ARBs vs. control: RD=-0.02, 95% CI=-0.07-0.03, Z=0.75, P=0.45). However, there was no significant difference in the serum potassium between ACEIs or ARBs group and control group in HD patients (ACEIs vs. control: WMD=0.10, 95% CI=0.06-0.15, Z=4.64, P<0.00001; ARBs vs. control: WMD=-0.24, 95% CI=-0.37-0.11, Z=3.58, P=0.0003). The use of ACEIs or ARBs could not cause an increased risk of hyperkalemia in HD patients, however the serum potassium could be increased with use of ACEIs in HD patients. Therefore the serum potassium concentration should still be closely monitored when ACEIs are taken during the maintenance HD.
Assuntos
Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Hiperpotassemia/induzido quimicamente , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise RenalRESUMO
Oxidative stress is associated with vascular remodeling and increased preglomerular resistance that are both implicated in the pathogenesis of renal and cardiovascular disease. Angiotensin II induces superoxide production, which is metabolized by superoxide dismutase (SOD) or scavenged by NO. We investigated the hypothesis that SOD1 regulates renal microvascular remodeling, blood pressure, and arteriolar responsiveness and sensitivity to angiotensin II using SOD1-transgenic (SOD1-tg) and SOD1-knockout (SOD1-ko) mice. Blood pressure, measured telemetrically, rose more abruptly during prolonged angiotensin II infusion in SOD1-ko mice. The afferent arteriole media:lumen ratios were reduced in SOD1-tg and increased in SOD1-ko mice. Afferent arterioles from nontreated wild types had graded contraction to angiotensin II (sensitivity: 10(-9) mol/L; responsiveness: 40%). Angiotensin II contractions were less sensitive (10(-8) mol/L) and responsive (14%) in SOD1-tg but more sensitive (10(-13) mol/L) and responsive (89%) in SOD1-ko mice. Arterioles from SOD1-ko had 4-fold increased superoxide formation with angiotensin II at 10(-9) mol/L. N(G)-nitro-l-arginine methyl ester reduced arteriole diameter of SOD1-tg and enhanced angiotensin II sensitivity and responsiveness of wild-type and SOD1-tg mice to the level of SOD1-ko mice. SOD mimetic treatment with Tempol increased arteriole diameter and normalized the enhanced sensitivity and responsiveness to angiotensin II of SOD1-ko mice but did not affect wild-type or SOD1-tg mice. Neither SOD1 deficiency nor overexpression was associated with changes in nitrate/nitrite excretion or renal mRNA expression of NO synthase, NADPH oxidase, or SOD2/SOD3 isoforms and angiotensin II receptors. In conclusion, SOD1 limits afferent arteriole remodeling and reduces sensitivity and responsiveness to angiotensin II by reducing superoxide and maintaining NO bioavailability. This may prevent an early and exaggerated blood pressure response to angiotensin II.
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Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Rim/metabolismo , Microvasos/metabolismo , Óxido Nítrico/metabolismo , Superóxido Dismutase/metabolismo , Análise de Variância , Animais , Pressão Sanguínea/genética , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microvasos/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Vasoconstritores/farmacologiaRESUMO
Many agents constrict isolated afferent arterioles only at concentrations higher than their physiological levels. Here we determined if norepinephrine, as released by sympathetic nerve activity, could influence the angiotensin II responsiveness of isolated mouse afferent arterioles. Pretreatment of the arterioles for short periods with norepinephrine significantly increased the ability of 10 picomolar angiotensin II to constrict the vessels, an effect inhibited by the alpha receptor blockers prazosin (alpha-1) or yohimbine (alpha-2). Although the intracellular calcium transients induced by angiotensin were not different, phosphorylation of the 20 kDa myosin light chain was significantly increased in the presence of norepinephrine. Phosphorylation of the p38 mitogen-activated protein kinase was not changed. Phosphorylation of the myosin phosphatase targeting subunit at Thr696, but not at Thr850, was significantly enhanced by, norepinephrine pretreatment, thus increasing the calcium sensitivity of the arteriolar smooth muscle. Our results show that norepinephrine increases afferent arteriolar sensitivity to angiotensin II by means of alpha receptor activation, causing increased calcium sensitivity through phosphorylation of the myosin phosphatase targeting subunit.
Assuntos
Angiotensina II/metabolismo , Sinalização do Cálcio , Rim/irrigação sanguínea , Norepinefrina/metabolismo , Circulação Renal , Vasoconstrição , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Arteríolas/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cadeias Leves de Miosina/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Perfusão , Fosforilação , Prazosina/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Circulação Renal/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Ioimbina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
NADPH oxidases (NOX) are the major source of reactive oxygen species (ROS) in the vasculature and contribute to the control of renal perfusion. The role of NOX2 in the regulation of blood pressure and afferent arteriole responsiveness was investigated in NOX2(-/-) and wild-type mice. Arteriole constrictions to ANG II (10(-14)-10(-6) mol/l) were weaker in NOX2(-/-) compared with wild types. N(omega)-nitro-l-arginine methyl ester (l-NAME; 10(-4) mol/l) treatment reduced basal diameters significantly more in NOX2(-/-) (-18%) than in wild types (-6%) and augmented ANG II responses. Adenosine (10(-11)-10(-4) mol/l) constricted arterioles of wild types but not of NOX2(-/-). However, simultaneous inhibition of adenosine type-2 receptors induced vasoconstriction, which was stronger in NOX2(-/-). Adenosine (10(-8) mol/l) enhanced the ANG II response in wild type, but not in NOX2(-/-). This sensitizing effect by adenosine was abolished by apocynin. Chronic ANG II pretreatment (14 days) did not change the ANG II responses in NOX2(-/-), but strengthened the response in wild types. ANG II pretreatment augmented the l-NAME response in NOX2(-/-) (-33%), but not in wild types. Simultaneous application of l-NAME and ANG II caused a stronger constriction in the NOX2(-/-) (-64%) than in wild types (-46%). Basal blood pressures were similar in both genotypes, however, chronic ANG II infusion elevated blood pressure to a greater extent in wild-type (15 +/- 1%) than in NOX2(-/-) (8 +/- 1%) mice. In conclusion, NOX2 plays an important role in the control of afferent arteriole tone and is involved in the contractile responses to ANG II and/or adenosine. NOX2 can be activated by elevated ANG II and may play an important role in ANG II-induced hypertension. NOX2-derived ROS scavenges nitric oxide, causing subsequent nitric oxide-deficiency.
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Hipertensão/fisiopatologia , Córtex Renal/irrigação sanguínea , Glicoproteínas de Membrana/metabolismo , NADPH Oxidases/metabolismo , Circulação Renal , Vasoconstrição , Acetofenonas/farmacologia , Adenosina/farmacologia , Angiotensina II/administração & dosagem , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/enzimologia , Pressão Sanguínea , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Bombas de Infusão Implantáveis , Infusões Subcutâneas , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/deficiência , NADPH Oxidases/genética , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Circulação Renal/efeitos dos fármacos , Superóxidos/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
Afferent arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N(G)-nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (-6%) but reduced it in control (-12%) and contralateral arterioles (-43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic arterioles (-18%) than in control (-42%) and contralateral arterioles (-49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (-19%) compared with control (-8%) and contralateral kidneys (+/-0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (-40%) was observed for all of the groups. This response was totally abolished in arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension.
Assuntos
Adenosina/fisiologia , Arteríolas/metabolismo , Hidronefrose/metabolismo , Hipertensão/metabolismo , Óxido Nítrico/deficiência , Angiotensina II/fisiologia , Animais , Arteríolas/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Hidronefrose/etiologia , Hidronefrose/patologia , Hipertensão/etiologia , Hipertensão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Estresse Oxidativo/fisiologia , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Fatores de Crescimento Transformadores/metabolismo , Vasoconstrição , Vasoconstritores/farmacologiaRESUMO
Adenosine triphosphate (ATP) and norepinephrine (NE) interact in the control of blood flow in the kidney. A combined effect of NE and ATP has not been previously investigated at the level of the afferent arteriole (Af). We studied the effects of ATP on the contractile response of the Af to NE. Vascular reactivity to ATP, NE, and their combination was investigated in isolated perfused Af from mice. The roles of alpha-adrenoceptors and P2-ATP-receptors were investigated by use of specific agonists and antagonists. Cytosolic calcium was measured using the fluorescent calcium dye fura-2. ATP in concentrations from 10(-12) to 10(-4) mol/l induced transient contractions. NE constricted the Af in a dose-dependent manner and induced significant contractions at > 10(-7) mol/l. Treatment with ATP (10(-8) and 10(-6) mol/l) increased the NE response. Diameters were reduced by 20% already at 10(-11) mol/l NE during ATP treatment of 10(-6) mol/l. ATP increased the calcium response to NE significantly at 10(-8) and 10(-7)mol/l NE. The P2-type ATP receptor blocker pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) (10(-5) mol/l) abolished the sensitization of the NE response by ATP. The alpha(1)-blocker prazosin (10(-7) mol/l) inhibited the ATP effect, as did the alpha 2-blocker yohimbine (10(-7) mol/l). Neither the phenylephrine- nor clonidine-induced concentration response curves was affected by ATP in the bath solution. Costimulation with ATP enhances the response of the Af to NE. This effect is mediated by increased cytosolic calcium. The enhancing effect involves P2-type ATP receptors and both alpha (1)- and alpha 2-adrenoceptors.