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1.
Blood Purif ; 52(11-12): 857-879, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37742622

RESUMO

In 2022, we celebrated the 15th anniversary of the University of Alabama at Birmingham (UAB) Continuous Renal Replacement Therapy (CRRT) Academy, a 2-day conference attended yearly by an international audience of over 100 nephrology, critical care, and multidisciplinary trainees and practitioners. This year, we introduce the proceedings of the UAB CRRT Academy, a yearly review of select emerging topics in the field of critical care nephrology that feature prominently in the conference. First, we review the rapidly evolving field of non-invasive hemodynamic monitoring and its potential to guide fluid removal by renal replacement therapy (RRT). We begin by summarizing the accumulating data associating fluid overload with harm in critical illness and the potential for harm from end-organ hypoperfusion caused by excessive fluid removal with RRT, underscoring the importance of accurate, dynamic assessment of volume status. We describe four applications of point-of-care ultrasound used to identify patients in need of urgent fluid removal or likely to tolerate fluid removal: lung ultrasound, inferior vena cava ultrasound, venous excess ultrasonography, and Doppler of the left ventricular outflow track to estimate stroke volume. We briefly introduce other minimally invasive hemodynamic monitoring technologies before concluding that additional prospective data are urgently needed to adapt these technologies to the specific task of fluid removal by RRT and to learn how best to integrate them into practical fluid-management strategies. Second, we focus on the growth of novel extracorporeal blood purification devices, starting with brief reviews of the inflammatory underpinnings of multiorgan dysfunction and the specific applications of pathogen, endotoxin, and/or cytokine removal and immunomodulation. Finally, we review a series of specific adsorptive technologies, several of which have seen substantial clinical use during the COVID-19 pandemic, describing their mechanisms of target removal, the limited existing data supporting their efficacy, ongoing and future studies, and the need for additional prospective trials.


Assuntos
Injúria Renal Aguda , Terapia de Substituição Renal Contínua , Insuficiência Cardíaca , Monitorização Hemodinâmica , Desequilíbrio Hidroeletrolítico , Humanos , Terapia de Substituição Renal Contínua/efeitos adversos , Estudos Prospectivos , Monitorização Hemodinâmica/efeitos adversos , Pandemias , Injúria Renal Aguda/terapia , Injúria Renal Aguda/etiologia , Terapia de Substituição Renal/efeitos adversos , Desequilíbrio Hidroeletrolítico/complicações , Insuficiência Cardíaca/complicações , Proliferação de Células
2.
BMC Nephrol ; 24(1): 299, 2023 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-37821813

RESUMO

BACKGROUND: Acute kidney injury (AKI) is a major burden among hospitalized and critical care patients. Among hospitalized patients that progress to severe AKI there is increased risk for morbidity, mortality, and the need for renal replacement therapy (RRT). As there are no specific treatments for AKI, the discovery of novel biomarkers that predict the progression of AKI may aid in timely implementation of supportive care to improve outcomes. METHODS: We collected urine from 204 patients that developed Stage 1 AKI by AKIN criteria within 72 h following cardiothoracic surgery. Urine samples were collected at the time of the initial diagnosis of AKI and stored at -80° C. Among the 204 patients, 25 progressed to a composite primary outcome of Stage 3 AKI, requirement of RRT, or 30-day mortality. The remaining 179 patients did not progress beyond Stage 2 AKI and were considered controls. Urinary concentrations of SOD1 and SOD1 activity were measured following collection of all samples. Samples were thawed and urinary superoxide dismutase 1 (SOD1) concentrations were measured by sandwich ELISA and urinary SOD1 activity was measured through a commercially available colorimetric assay. RESULTS: Urinary concentrations of SOD1 were significantly elevated (67.0 ± 10.1 VS 880.3 ± 228.8 ng/ml, p < 0.0001) in patients that progressed to severe AKI and were able to predict the progression to severe AKI (AUC - 0.85, p < 0.0001). Furthermore, total SOD activity also increased in the urine of patients that required RRT (77.6% VS 49.81% median inhibition, p < 0.01) and was able to predict the need for RRT (AUC: 0.83, p < 0.01). CONCLUSION: These findings show that urinary SOD1 concentrations and SOD activity are novel prognostic biomarkers for severe AKI following cardiothoracic surgery.


Assuntos
Injúria Renal Aguda , Humanos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Biomarcadores/urina , Prognóstico , Terapia de Substituição Renal , Superóxido Dismutase-1
3.
N Engl J Med ; 381(1): 36-46, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31269364

RESUMO

BACKGROUND: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).


Assuntos
Ciclosporina/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Imunossupressores/uso terapêutico , Rituximab/uso terapêutico , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclosporina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/efeitos adversos , Infusões Intravenosas , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteinúria/tratamento farmacológico , Indução de Remissão , Rituximab/efeitos adversos , Falha de Tratamento , Adulto Jovem
4.
Am J Kidney Dis ; 79(5): 737-745, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34606933

RESUMO

Hepatorenal syndrome (HRS) is a form of acute kidney injury (AKI) occurring in patients with advanced cirrhosis and is associated with significant morbidity and mortality. The pathophysiology underlying HRS begins with increasing portal pressures leading to the release of vasodilatory substances that result in pooling blood in the splanchnic system and a corresponding reduction in effective circulating volume. Compensatory activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and release of arginine vasopressin serve to defend mean arterial pressure but at the cost of severe constriction of the renal vasculature, leading to a progressive, often fulminant form of AKI. There are no approved treatments for HRS in the United States, but multiple countries, including much of Europe, use terlipressin, a synthetic vasopressin analogue, as a first-line therapy. CONFIRM (A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1), the third randomized trial based in North America evaluating terlipressin, met its primary end point of showing greater rates of HRS reversal in the terlipressin arm. However, due to concerns about the apparent increased rates of respiratory adverse events and a lack of evidence for mortality benefit, terlipressin was not approved by the Food and Drug Administration (FDA). We explore the history of regulatory approval for terlipressin in the United States, examine the results from CONFIRM and the concerns they raised, and consider the future role of terlipressin in this critical clinical area of continued unmet need.


Assuntos
Injúria Renal Aguda , Síndrome Hepatorrenal , Injúria Renal Aguda/induzido quimicamente , Feminino , Síndrome Hepatorrenal/tratamento farmacológico , Humanos , Lipressina/uso terapêutico , Masculino , Terlipressina/uso terapêutico , Resultado do Tratamento , Vasoconstritores/uso terapêutico
5.
J Am Soc Nephrol ; 32(10): 2485-2500, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34127535

RESUMO

BACKGROUND: Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the ß-splice variant of nitric oxide synthase 1 (NOS1ß) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1ß in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease. METHODS: We used sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of renal tubules in vivo, clearance kinetics of plasma FITC-sinistrin, and radiotelemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1ß/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice. RESULTS: Macula densa NOS1ß was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1ß, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1ß expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies. CONCLUSIONS: Macula densa NOS1ß plays a critical role in the control of renal hemodynamics and BP during pregnancy.


Assuntos
Pressão Arterial , Hipertensão Induzida pela Gravidez/fisiopatologia , Glomérulos Renais/fisiopatologia , Túbulos Renais Distais/fisiopatologia , Óxido Nítrico Sintase Tipo I/metabolismo , Animais , Chlorocebus aethiops , Retroalimentação Fisiológica , Feminino , Taxa de Filtração Glomerular , Hipertensão Induzida pela Gravidez/metabolismo , Hipertensão Induzida pela Gravidez/patologia , Isoenzimas , Túbulos Renais Distais/metabolismo , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo I/genética , Gravidez , Circulação Renal , Regulação para Cima , Útero/irrigação sanguínea
6.
Semin Dial ; 34(6): 406-415, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33939859

RESUMO

The advances in the technology for providing continuous renal replacement therapy (CRRT) have led to an increase in its utilization throughout the world. However, circuit life continues to be a major problem. It leads not only to decreased delivery of dialysis but also causes blood loss, waste of disposables, alters dose delivery of medications and nutrition, and increases nurse workload, all of which increases healthcare cost. Premature circuit failure can be caused by numerous factors that can be difficult to dissect out. The first component is the vascular access; without a well-placed, functioning access, delivery of CRRT becomes very difficult. This is usually accomplished by placing a short-term dialysis catheter into either the right internal jugular or femoral vein. The tips should be located at the caval atrial junction or inferior vena cava. In addition to establishing suitable vascular access, a comprehensive understanding of the circuit facilitates the development of a methodical approach in providing efficient CRRT characterized by optimal circuit life. Moreover, it aids in determining the cause of circuit failure in patients experiencing recurrent episodes. This review therefore summarizes the essential points that guide providers in establishing optimal vascular access. We then provide an overview of the main components of the CRRT circuit including the blood and fluid pumps, the hemofilter, and pressure sensors, which will assist in identifying the key mechanisms contributing to premature failure of the CRRT circuit.


Assuntos
Terapia de Substituição Renal Contínua , Cateterismo , Humanos , Diálise Renal , Terapia de Substituição Renal
7.
Int J Mol Sci ; 20(15)2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31382550

RESUMO

Reactive oxygen species (ROS) are highly reactive signaling molecules that maintain redox homeostasis in mammalian cells. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of ROS, culminating in oxidative stress and the associated oxidative damage of cellular components. ROS and oxidative stress play a vital role in the pathogenesis of acute kidney injury and chronic kidney disease, and it is well documented that increased oxidative stress in patients enhances the progression of renal diseases. Oxidative stress activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular oxidized and damaged macromolecules and dysfunctional organelles. In this review, we report the current understanding of the molecular regulation of autophagy in response to oxidative stress in general and in the pathogenesis of kidney diseases. We summarize how the molecular interactions between ROS and autophagy involve ROS-mediated activation of autophagy and autophagy-mediated reduction of oxidative stress. In particular, we describe how ROS impact various signaling pathways of autophagy, including mTORC1-ULK1, AMPK-mTORC1-ULK1, and Keap1-Nrf2-p62, as well as selective autophagy including mitophagy and pexophagy. Precise elucidation of the molecular mechanisms of interactions between ROS and autophagy in the pathogenesis of renal diseases may identify novel targets for development of drugs for preventing renal injury.


Assuntos
Injúria Renal Aguda/genética , Autofagia/genética , Estresse Oxidativo/genética , Insuficiência Renal Crônica/genética , Quinases Proteína-Quinases Ativadas por AMP , Injúria Renal Aguda/patologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Fator 2 Relacionado a NF-E2/genética , Proteínas Quinases/genética , Proteínas de Ligação a RNA/genética , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/patologia
8.
Nephrol Dial Transplant ; 33(3): 392-401, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28402508

RESUMO

Background: African American (AA) subjects with essential hypertension (EH) have greater inflammation and cardiovascular complications than Caucasian EH. An impaired endogenous cellular repair system may exacerbate vascular injury in hypertension, yet whether these differ between AA EH and Caucasian EH remains unknown. Vascular repair by circulating endothelial progenitor cells (EPCs) is controlled by regulators of EPC mobilization, homing, adhesion and new vessel formation, but can be hindered by various cytokines. We hypothesized that EPC levels and function would be impaired in AA EH compared with Caucasian EH, in association with increased levels of inflammatory mediators and EPC regulators. Methods: CD34+/KDR+ EPCs were isolated from inferior vena cava and renal vein blood samples of AA EH and Caucasian EH patients (n = 18 each) and from peripheral veins of 17 healthy volunteers (HVs) and enumerated using fluorescence-activated cell sorting. Angiogenic function of late-outgrowth endothelial cells expanded from these samples for 3 weeks was tested in vitro. Levels of inflammatory mediators, angiogenic factors and EPC regulators were measured by Luminex. Results: EPC levels were decreased in both AA and Caucasian EH compared with HVs, whereas their late-outgrowth endothelial cell angiogenic function was comparable. Levels of several inflammatory mediators were elevated in AA EH compared with Caucasian EH and HVs. Contrarily, vascular endothelial growth factor and its receptor-2 were lower. EPC levels inversely correlated with blood pressure in all hypertensive patients and estimated glomerular filtration rate with inflammatory mediators only in AA EH. Conclusions: Despite lower EPC numbers, decreased vascular endothelial growth factor signaling and inflammation, EPC function is preserved in AA EH compared with Caucasian EH and HVs, suggesting compensatory mechanisms for vascular repair.


Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Células Progenitoras Endoteliais/citologia , Hipertensão Essencial/fisiopatologia , Inflamação/patologia , Neovascularização Fisiológica , Fator A de Crescimento do Endotélio Vascular/metabolismo , População Branca/estatística & dados numéricos , Idoso , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Células Cultivadas , Células Progenitoras Endoteliais/metabolismo , Hipertensão Essencial/metabolismo , Feminino , Taxa de Filtração Glomerular , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
9.
Semin Dial ; 31(1): 88-93, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28762237

RESUMO

The current standard of care for prosthetic joint infection includes two-stage arthroplasty, with antibiotic-impregnated cement spacers (ACS) utilized between the stages. We report a 75-year-old woman with previously normal renal function, who developed acute kidney injury (AKI) secondary to biopsy-proven acute tubular necrosis and acute interstitial nephritis after ACS placement containing tobramycin and vancomycin. Peak tobramycin level measured 25.3 mcg/mL, the highest value reported in the literature after ACS placement. Intermittent hemodialysis was initiated with subsequent full recovery of renal function. This paper reviews the published literature regarding the accumulation, toxicity and removal dynamics of aminoglycoside (AG) antibiotics and vancomycin in renal patients. Obtaining serum AG level should be strongly considered in patients experiencing AKI after ACS. Renal replacement therapy may assist in reducing toxic AG levels.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/terapia , Aminoglicosídeos/efeitos adversos , Hemiartroplastia/efeitos adversos , Infecções Relacionadas à Prótese/terapia , Diálise Renal/métodos , Injúria Renal Aguda/patologia , Idoso , Aminoglicosídeos/farmacologia , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Biópsia por Agulha , Cimentos Ósseos , Feminino , Hemiartroplastia/métodos , Fraturas do Quadril/diagnóstico por imagem , Fraturas do Quadril/cirurgia , Humanos , Imuno-Histoquímica , Prognóstico , Infecções Relacionadas à Prótese/diagnóstico por imagem , Medição de Risco , Resultado do Tratamento
10.
BMC Nephrol ; 18(1): 222, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28683729

RESUMO

BACKGROUND: Continuous renal replacement therapy (CRRT) is the recommended modality of dialysis for critically ill patients with hemodynamic instability. Yet there remains significant variability in how CRRT is prescribed and delivered, and limited evidence-basis to guide practice. METHODS: This is a prospective, multi-center observational study of patients undergoing CRRT. Initial enrollment phase will occur at 4 academic medical centers in North America over 5 years, with a target enrollment of 2000 patients. All adult patients (18-89 years of age) receiving CRRT will be eligible for inclusion; patients who undergo CRRT for less than 24 h will be excluded from analysis. Data collection will include patient characteristics at baseline and at time of CRRT initiation; details of CRRT prescription and delivery, including machine-generated treatment data; and patient outcomes. DISCUSSION: The goal of this study is to establish a large comprehensive registry of critically ill adults receiving CRRT. Specific aims include describing variations in CRRT prescription and delivery across quality domains; validating quality measures for CRRT care by correlating processes and outcomes; and establishing a large registry for use in quality improvement and benchmarking efforts. For initial analyses, some particular areas of interest are anticoagulation protocols; approach to fluid overload; CRRT-related workload; and patient safety. TRIAL REGISTRATION: Registered on ClinicalTrials.gov 1/10/2014: NCT02034448.


Assuntos
Injúria Renal Aguda/terapia , Estado Terminal/terapia , Terapia de Substituição Renal/métodos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Estado Terminal/epidemiologia , Humanos , Estudos Prospectivos , Terapia de Substituição Renal/tendências
11.
J Am Soc Nephrol ; 27(8): 2346-56, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26647426

RESUMO

Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α-, ß-, and γ-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1ß expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1ß expression in the macula densa affects sodium excretion and salt-sensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1ß mRNA and protein were 30- and five-fold higher, respectively, than those of NOS1α in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1α-knockout (NOS1αKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P<0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P<0.01) fed a high-salt diet. These results indicate that NOS1ß is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.


Assuntos
Hipertensão/enzimologia , Hipertensão/etiologia , Sistema Justaglomerular/enzimologia , Óxido Nítrico Sintase Tipo I/fisiologia , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Hipertensão/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo I/uso terapêutico
12.
Am J Physiol Renal Physiol ; 311(2): F395-403, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27252490

RESUMO

Renal ischemia-reperfusion (I/R) in male rats causes reductions in plasma testosterone, and infusion of testosterone 3 h postreperfusion is protective. We tested the hypotheses that acute high doses of testosterone promote renal injury after I/R, and that acute low-dose testosterone is protective by the following: 1) increasing renal IL-10 and reducing TNF-α; 2) its effects on nitric oxide; and 3) reducing intrarenal T-cell infiltration. Rats were subjected to renal I/R, followed by intravenous infusion of vehicle or testosterone (20, 50, or 100 µg/kg) 3 h postreperfusion. Low-dose testosterone (20 µg/kg) reduced plasma creatinine, increased nitrate/nitrite excretion, increased intrarenal IL-10, and reduced intrarenal TNF-α, whereas 50 µg/kg testosterone failed to reduce plasma creatinine, increased IL-10, but failed to reduce TNF-α. A higher dose of testosterone (100 mg/kg) not only failed to reduce plasma creatinine, but significantly increased both IL-10 and TNF-α compared with other groups. Low-dose nitro-l-arginine methyl ester (1 mg·kg(-1)·day(-1)), given 2 days before I/R, prevented low-dose testosterone (20 µg/kg) from protecting against I/R injury, and was associated with lack of increase in intrarenal IL-10. Intrarenal CD4(+) and CD8(+) T cells were significantly increased with I/R, but were attenuated with low-dose testosterone, as were effector T helper 17 cells. The present studies suggest that acute, low-dose testosterone is protective against I/R AKI in males due to its effects on inflammation by reducing renal T-cell infiltration and by shifting the balance to favor anti-inflammatory cytokine production rather than proinflammatory cytokines.


Assuntos
Interleucina-10/metabolismo , Nefropatias/prevenção & controle , Rim/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Linfócitos T/efeitos dos fármacos , Testosterona/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Animais , Creatina/sangue , Citocinas/biossíntese , Inibidores Enzimáticos/uso terapêutico , Nefropatias/patologia , Masculino , NG-Nitroarginina Metil Éster/uso terapêutico , Nitratos/sangue , Óxido Nítrico Sintase/antagonistas & inibidores , Nitritos/sangue , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Testosterona/administração & dosagem , Células Th17/efeitos dos fármacos
13.
J Am Soc Nephrol ; 26(10): 2460-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25644108

RESUMO

Ischemia-reperfusion (IR) injury is the most common cause of AKI. The susceptibility to develop AKI varies widely among patients. However, little is known about the genes involved. 20-Hydroxyeicosatetraenoic acid (20-HETE) has an important role in the regulation of renal tubular and vascular function and has been implicated in IR injury. In this study, we examined whether a deficiency in the renal formation of 20-HETE enhances the susceptibility of Dahl salt-sensitive (SS) rats to ischemic AKI. Transfer of chromosome 5 containing the CYP4A genes responsible for the formation of 20-HETE from the Brown Norway (BN) rat onto the SS genetic background increased renal 20-HETE levels after ischemia and reduced plasma creatinine levels (±SEM) 24 hours after IR from 3.7±0.1 to 2.0±0.2 mg/dl in an SS.5(BN)-consomic strain. Transfer of this chromosome also prevented the secondary decline in medullary blood flow and ischemia that develops 2 hours after IR in the susceptible SS strain. Blockade of the synthesis of 20-HETE with HET0016 reversed the renoprotective effects in SS.5(BN) rats. Similar results were observed in an SS.5(Lew)-congenic strain, in which a smaller region of chromosome 5 containing the CYP4A genes from a Lewis rat was introgressed onto the SS genetic background. These results indicate that 20-HETE has a protective role in renal IR injury by maintaining medullary blood flow and that a genetic deficiency in the formation of 20-HETE increases the susceptibility of SS rats to ischemic AKI.


Assuntos
Ácidos Hidroxieicosatetraenoicos/deficiência , Rim/irrigação sanguínea , Traumatismo por Reperfusão/etiologia , Injúria Renal Aguda/etiologia , Animais , Citocromo P-450 CYP4A/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Ácidos Hidroxieicosatetraenoicos/biossíntese , Ácidos Hidroxieicosatetraenoicos/genética , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações
14.
Am J Physiol Regul Integr Comp Physiol ; 309(7): R757-66, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26269519

RESUMO

The present study tested whether primary cilia on macula densa serve as a flow sensor to enhance nitric oxide synthase 1 (NOS1) activity and inhibit tubuloglomerular feedback (TGF). Isolated perfused macula densa was loaded with calcein red and 4,5-diaminofluorescein diacetate to monitor cell volume and nitric oxide (NO) generation. An increase in tubular flow rate from 0 to 40 nl/min enhanced NO production by 40.0 ± 1.2%. The flow-induced NO generation was blocked by an inhibitor of NOS1 but not by inhibition of the Na/K/2Cl cotransporter or the removal of electrolytes from the perfusate. NO generation increased from 174.8 ± 21 to 276.1 ± 24 units/min in cultured MMDD1 cells when shear stress was increased from 0.5 to 5.0 dynes/cm(2). The shear stress-induced NO generation was abolished in MMDD1 cells in which the cilia were disrupted using a siRNA to ift88. Increasing the NaCl concentration of the tubular perfusate from 10 to 80 mM NaCl in the isolated perfused juxtaglomerular preparation reduced the diameter of the afferent arteriole by 3.8 ± 0.1 µm. This response was significantly blunted to 2.5 ± 0.2 µm when dextran was added to the perfusate to increase the viscosity and shear stress. Inhibition of NOS1 blocked the effect of dextran on TGF response. In vitro, the effects of raising perfusate viscosity with dextran on tubular hydraulic pressure were minimized by reducing the outflow resistance to avoid stretching of tubular cells. These results suggest that shear stress stimulates primary cilia on the macula densa to enhance NO generation and inhibit TGF responsiveness.


Assuntos
Cílios/fisiologia , Retroalimentação Fisiológica/fisiologia , Glomérulos Renais/metabolismo , Glomérulos Renais/fisiologia , Túbulos Renais/metabolismo , Túbulos Renais/fisiologia , Óxido Nítrico/metabolismo , Estresse Mecânico , Animais , Contagem de Células , Linhagem Celular , Concentração de Íons de Hidrogênio , Glomérulos Renais/irrigação sanguínea , Túbulos Renais/irrigação sanguínea , Masculino , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo I/metabolismo , RNA Interferente Pequeno/farmacologia , Coelhos , Viscosidade
15.
Am J Physiol Renal Physiol ; 306(3): F344-50, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24285500

RESUMO

NAD(P)H oxidase (Nox)2 and Nox4 are the isoforms of Nox expressed in the macula densa (MD). MD-derived superoxide (O2⁻), primarily generated by Nox2, is enhanced by acute ANG II stimulation. However, the effects of chronic elevations in ANG II during ANG II-induced hypertension on MD-derived O2⁻ are unknown. We infused a slow pressor dose of ANG II (600 ng·min⁻¹·kg⁻¹) for 2 wk in C57BL/6 mice and found that mean arterial pressure was elevated by 22.3 ± 3.4 mmHg (P < 0.01). We measured O2⁻ generation in isolated and perfused MDs and found that O2⁻ generation by the MD was increased from 9.4 ± 0.9 U/min in control mice to 34.7 ± 1.8 U/min in ANG II-induced hypertensive mice (P < 0.01). We stimulated MMDD1 cells, a MD-like cell line, with ANG II and found that O2⁻ generation increased from 921 ± 91 to 3,687 ± 183 U·min⁻¹·105 cells⁻¹, which was inhibited with apocynin, oxypurinol, or NS-398 by 46%, 14%, and 12%, respectively. We isolated MD cells using laser capture microdissection and measured mRNA levels of Nox. Nox2 and Nox4 levels increased by 3.7 ± 0.17- and 2.6 ± 0.15-fold in ANG II-infused mice compared with control mice. In MMDD1 cells treated with Nox2 or Nox4 small interfering (si)RNAs, ANG II-stimulated O2⁻ generation was blunted by 50% and 41%, respectively. In cells treated with p22(phox) siRNA, ANG II-stimulated O2⁻ generation was completely blocked. In conclusion, we found that a subpressor dose of ANG II enhances O2⁻ generation in the MD and that the sources of this O2⁻ are primarily Nox2 and Nox4.


Assuntos
Hipertensão/enzimologia , Sistema Justaglomerular/metabolismo , Túbulos Renais Distais/metabolismo , Glicoproteínas de Membrana/metabolismo , NADPH Oxidases/metabolismo , Superóxidos/metabolismo , Angiotensina II/farmacologia , Animais , Linhagem Celular , Hipertensão/induzido quimicamente , Isoenzimas/metabolismo , Glicoproteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/biossíntese , RNA Mensageiro/metabolismo
16.
Clin Exp Hypertens ; 36(3): 132-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23786429

RESUMO

BACKGROUND/AIM: Renal preglomerular vessels play a central role in modulating renal function and injury, especially during conditions of renal hemodynamic stress such as hypertension. We evaluated whether improving the balance between nitric oxide (NO) and oxidative stress improves the morphological alterations of renal afferent arterioles that occur in NO deficiency-induced hypertension. METHODS: We measured indices of NO and oxidative stress and evaluated renal morphology and afferent arteriolar remodeling in rats treated with vehicle, L-NAME or L-NAME plus tempol (a superoxide dismutase mimetic) for 6 weeks. RESULTS: L-NAME-treated rats had hypertension, lower urinary and renal NO indices, higher renal cortical levels of TBARS, GSSG and GSSG/GSH. This was associated with significant eutrophic inward remodeling of the afferent arterioles; they had a marked decrease in arteriolar lumen area and a striking increase in arteriolar wall thickness and media to lumen ratio. Tempol did not significantly reduce blood pressure, but increased NO levels, decreased oxidative stress and partially blunted L-NAME-induced remodeling of afferent arterioles. CONCLUSION: L-NAME-induced remodeling of afferent arterioles is blunted by tempol. This beneficial effect on remodeling is associated with increases in NO indices, decreases in oxidative stress, without significant decreases in blood pressure. Thus, the balance between these components may contribute to the altered renal hemodynamics and function in this model.


Assuntos
Arteríolas/efeitos dos fármacos , Óxidos N-Cíclicos/farmacologia , Hipertensão/tratamento farmacológico , Óxido Nítrico/deficiência , Remodelação Vascular , Animais , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Marcadores de Spin
17.
Am J Physiol Regul Integr Comp Physiol ; 304(11): R951-8, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23552495

RESUMO

Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease, in general. In the present study, we tested the hypothesis that I/R of the kidney reduces serum testosterone, and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 h after reperfusion that remained at 24 h. Acute infusion of testosterone 3 h after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 h, prevented the reduction in outer medullary blood flow, and attenuated the increase in intrarenal TNF-α and the decrease in intrarenal VEGF at 48 h. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 h than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney, whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol.


Assuntos
Injúria Renal Aguda/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Testosterona/farmacologia , Injúria Renal Aguda/fisiopatologia , Anastrozol , Animais , Inibidores da Aromatase/farmacologia , Moléculas de Adesão Celular/urina , Creatinina/sangue , Masculino , Nitrilas/farmacologia , Orquiectomia , Proteinúria/sangue , Ratos , Ratos Sprague-Dawley , Circulação Renal/fisiologia , Traumatismo por Reperfusão/fisiopatologia , Testosterona/sangue , Testosterona/uso terapêutico , Triazóis/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Am J Nephrol ; 38(3): 226-32, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23988748

RESUMO

BACKGROUND/AIMS: Adult and childhood obesity is an independent risk factor in development of chronic kidney disease (CKD) and its progression to end-stage kidney disease. Pathologic consequences of obesity include non-esterified fatty acid-induced oxidative stress and consequent injury. Since the serine36-phosphorylated p66shc is a newly recognized mediator of oxidative stress and kidney injury, we studied its role in oleic acid (OA)-induced production of reactive oxygen species (ROS), mitochondrial depolarization and injury in cultured renal proximal tubule cells. METHODS: Renal proximal tubule cells were used and treated with OA: ROS production, mitochondrial depolarization as well as injury were determined. Transcriptional effects of OA on the p66shc gene were determined in a reporter luciferase assay. The role of p66shc in adverse effects of OA was determined using knockdown, p66shc serine36 phosphorylation and cytochrome c binding-deficient cells. RESULTS: We found that OA increased ROS production via the mitochondria - and to a less extent via the NADPH oxidase - resulting in ROS-dependent mitochondrial depolarization and consequent injury. Interestingly, OA also stimulated the promoter of p66shc. Hence, knockdown of p66shc, impairment its Ser36 phosphorylation (mutation of Ser36 residue to alanine) or cytochrome c binding (W134F mutation) significantly attenuated OA-dependent lipotoxicity. CONCLUSION: These results offer a novel mechanism by which obesity may lead to renal tubular injury and consequently development of CKD. Manipulation of this pathway may offer therapeutic means to ameliorate obesity-dependent renal lipotoxicity.


Assuntos
Rim/efeitos dos fármacos , Rim/metabolismo , Ácido Oleico/toxicidade , Proteínas Adaptadoras da Sinalização Shc/fisiologia , Animais , Linhagem Celular , Citocromos c/metabolismo , Relação Dose-Resposta a Droga , Túbulos Renais/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Camundongos , Mitocôndrias/metabolismo , NADPH Oxidases/metabolismo , Obesidade/metabolismo , Fosforilação , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , Espécies Reativas de Oxigênio , Fatores de Risco , Serina/química , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src
19.
Nephrol Dial Transplant ; 28(6): 1417-25, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23328708

RESUMO

BACKGROUND: Chronic nicotine (Ch-NIC) exposure exacerbates ischemia/reperfusion (I/R)-induced oxidative stress and acute kidney injury (AKI), and mitochondrial production of reactive oxygen species (ROS) in cultured renal proximal tubule cells (RPTCs). Because Ser36-phosphorylated p66shc modulates mitochondrial ROS production and injury of RPTCs, we hypothesized that Ch-NIC exacerbates AKI by increasing stress-induced phosphorylation of p66shc. METHODS: We first tested whether Ch-NIC augments I/R-AKI-induced expression and phosphorylation of p66shc in vivo. We then examined whether knocking down p66shc, or impairing its Ser36 phosphorylation or binding to cytochrome c, alters the effects of Ch-NIC on oxidative stress (H2O2)-induced production of ROS, mitochondrial depolarization and injury in RPTCs in vitro. RESULTS: We found that Ch-NIC increased the expression of p66shc in the control and ischemic kidneys, but only increased its Ser36 phosphorylation after renal I/R. Knocking down p66shc or impairing phosphorylation of its Ser36 residue, via the S36A mutation (but not the phosphomimetic S36D mutation), blunted Ch-NIC + H2O2-dependent ROS production, mitochondrial depolarization and injury in RPTCs. Additionally, Ch-NIC + H2O2-dependent binding of p66shc to mitochondrial cytochrome c was attenuated by S36A mutation of p66shc, and impairing cytochrome c binding (via W134F mutation) abolished ROS production, mitochondrial depolarization and injury, while ectopic overexpression of p66shc (which mimics Ch-NIC treatment) augmented oxidant injury. We determined that Ch-NIC stimulates the p66shc promoter through p53- and epigenetic modification (promoter hypomethylation). CONCLUSIONS: Ch-NIC worsens oxidative stress-dependent acute renal injury by increasing expression and consequent oxidative stress-dependent Ser36 phosphorylation of p66shc. Thus, targeting this pathway may have therapeutic relevance in preventing/ameliorating tobacco-related kidney injury.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Túbulos Renais Proximais/efeitos dos fármacos , Nicotina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/induzido quimicamente , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Western Blotting , Células Cultivadas , Citocromos c/metabolismo , Peróxido de Hidrogênio/metabolismo , Imunoprecipitação , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Luciferases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Agonistas Nicotínicos/toxicidade , Fosforilação Oxidativa , Fosforilação , Regiões Promotoras Genéticas/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Serina/metabolismo , Proteínas Adaptadoras da Sinalização Shc/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Ativação Transcricional
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