RESUMEN
OBJECTIVES: Several therapeutic agents have been developed and used for the clinical treatment of systemic lupus erythematosus (SLE). In cases where SLE is accompanied by severe organ failures, such as neuropsychiatric lupus erythematosus (NPSLE) and acute onset of lupus nephritis, the use of potent immunosuppressive drugs, such as cyclophosphamide, is necessary. However, potent immunosuppressive drugs are known to increase infection risks. Thus, the development of therapeutic agents with novel mechanisms is urgently required. Previously, we reported that treatment with lysophosphatidic acid (LPA) prevents depression-like behaviours by suppressing microglial activation in MRL/lpr mice. In this study, we examined whether the treatment with LPA improves glomerulonephritis by affecting systemic immunity in MRL/lpr mice. METHODS: Eighteen-week-old MRL/lpr mice were treated with a vehicle or LPA for 3 weeks. After treatment, the glomerular inflammation and damage parameters were compared between the 2 groups. Moreover, we examined the effects of LPA on immune cells by flow cytometry using isolated splenocytes. RESULTS: LPA treatment in MRL/lpr mice significantly reduced the daily urinary albumin content and suppressed the CD68-positive cells and Periodic acid-Schiff (PAS)-positive areas in the glomeruli. The treatment also suppressed plasma anti-dsDNA antibodies and inflammatory cytokines in MRL/lpr mice. Although LPA did not significantly affect the total number of splenocytes, the treatment significantly reduced CD11b+Ly6G-Ly6C- cells (mature macrophages), as well as CD11b+Ly6G-Ly6C-CD68+ cells (activated mature macrophages). CONCLUSIONS: These results suggest that LPA may improve glomerulonephritis by suppressing macrophage activation in MRL/lpr mice.
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Glomerulonefritis , Lupus Eritematoso Sistémico , Nefritis Lúpica , Lisofosfolípidos , Animales , Ratones , Modelos Animales de Enfermedad , Activación de Macrófagos , Ratones Endogámicos MRL lpr , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/prevención & control , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/prevención & control , Inmunosupresores/farmacología , Inmunosupresores/uso terapéuticoRESUMEN
Interleukin (IL)-1 receptor type 1 (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated podocyte IL-1R1 in mice (PKO mice). We then subjected PKO mice and wild-type controls to two glomerular injury models: nephrotoxic serum (NTS)- and adriamycin-induced nephropathy. Surprisingly, we found that IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and adriamycin-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between wild-type and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease.NEW & NOTEWORTHY The present study establishes that activation of the receptor for interleukin-1 limits susceptibility to damage to the kidney glomerulus in preclinical mouse models by stimulating Akt signaling cascades inside the podocyte.
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Glomerulonefritis/metabolismo , Podocitos/metabolismo , Proteinuria/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Doxorrubicina , Glomerulonefritis/inducido químicamente , Glomerulonefritis/patología , Glomerulonefritis/prevención & control , Humanos , Interleucina-1beta/farmacología , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Ratones de la Cepa 129 , Ratones Noqueados , Podocitos/efectos de los fármacos , Podocitos/patología , Proteinuria/inducido químicamente , Proteinuria/patología , Proteinuria/prevención & control , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Tipo I de Interleucina-1/agonistas , Receptores Tipo I de Interleucina-1/genética , Transducción de SeñalRESUMEN
Glomerulonephritis is an acquired serious glomerular disease, which involves the interplay of many factors such as cytokines, chemokines, inflammatory cells, and heparan sulfate (HS). We previously showed that blocking of inflammatory heparan sulfate domains on cultured glomerular endothelium by specific anti-HS single chain antibodies reduced polymorphonuclear cell (PMN) adhesion and chemokine binding. We hypothesized that injection of anti-HS antibodies in PMN-driven experimental glomerulonephritis should reduce glomerular influx of PMNs and thereby lead to a better renal outcome. In contrast to our hypothesis, co-injection of anti-HS antibodies did not alter the final outcome of anti-glomerular basement membrane (anti-GBM)-induced glomerulonephritis. Glomerular PMN influx, normally peaking 2 hours after induction of glomerulonephritis with anti-GBM IgG was not reduced by co-injection of anti-HS antibodies. Four days after induction of glomerulonephritis, albuminuria, renal function, glomerular hyalinosis and fibrin deposition were similar in mice treated and not treated with anti-HS antibodies. Interestingly, we observed transient effects in mice co-injected with anti-HS antibodies compared to mice that did not receive anti-HS antibodies: (i) a decreased renal function 2 hours and 1 day after induction of glomerulonephritis; (ii) an increased albuminuria after 2 hours and 1 day; (iii) an increased glomerular fibrin deposition after 1 day; (iv) a reduced glomerular macrophage influx after 1 day; (v) a sustained glomerular presence of PMNs at day 1 and 4, accompanied by an increased renal expression of IL-6, CXCL1, ICAM-1, L-selectin, CD11b and NF-κB. The mechanism underlying these observations induced by anti-HS antibodies remains unclear, but may be explained by a temporarily altered glycocalyx and/or altered function of PMNs due to the binding of anti-HS antibodies. Nevertheless, the evaluated anti-HS antibodies do not show therapeutic potential in anti-GBM-induced glomerulonephritis. Future research should evaluate other strategies to target HS domains involved in inflammatory processes during glomerulonephritis.
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Glomerulonefritis/metabolismo , Glomérulos Renales/metabolismo , Anticuerpos de Cadena Única/farmacología , Animales , Antígeno CD11b/biosíntesis , Quimiocina CXCL1/biosíntesis , Fibrina/metabolismo , Regulación de la Expresión Génica , Glomerulonefritis/patología , Glomerulonefritis/prevención & control , Heparitina Sulfato , Molécula 1 de Adhesión Intercelular/biosíntesis , Interleucina-6/biosíntesis , Glomérulos Renales/patología , Selectina L/biosíntesis , RatonesRESUMEN
BACKGROUND: Adiponectin is an adipocytokine that plays a key regulatory role in glucose and lipid metabolism in obesity. The prevalence of obesity has led to an increase in the incidence of obesity-related glomerulopathy (ORG). This study aimed to identify the protective role of adiponectin in ORG. METHODS: Small-interfering RNA (siRNA) against the gene encoding adiponectin was transfected into podocytes. The oxidative stress level was determined using a fluorometric assay. Apoptosis was analyzed by flow cytometry. The expressions of podocyte markers and pyrin domain containing protein 3 (NLRP3) inflammasome-related proteins were measured by qRT-PCR, immunohistochemistry, and Western blot. RESULTS: Podocytes treated with palmitic acid (PA) showed downregulated expressions of podocyte markers, increased apoptosis, upregulated levels of NLRP3 inflammasome-related proteins, increased production of inflammatory cytokines (IL-18 and IL-1ß), and induced activation of NF-κB as compared to the vehicle-treated controls. Decreased adiponectin expression was observed in the serum samples from high fat diet (HFD)-fed mice. Decreased podocin expression and upregulated NLRP3 expression were observed in the kidney samples from high fat diet (HFD)-fed mice. Treatment with adiponectin or the NLRP3 inflammasome inhibitor, MCC950, protected cultured podocytes against podocyte apoptosis and inflammation. Treatment with adiponectin protected mouse kidney tissues against decreased podocin expression and upregulated NLRP3 expression. The knockout of adiponectin gene by siRNA increased ROS production, resulting in the activation of NLRP3 inflammasome and the phosphorylation of NF-κB in podocytes. Pyrrolidine dithiocarbamate, an NF-κB inhibitor, prevented adiponectin from ameliorating FFA-induced podocyte injury and NLRP3 activation. CONCLUSIONS: Our study showed that adiponectin ameliorated PA-induced podocyte injury in vitro and HFD-induced injury in vivo via inhibiting the ROS/NF-κB/NLRP3 pathway. These data suggest the potential use of adiponectin for the prevention and treatment of ORG.
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Adiponectina/farmacología , Adiponectina/fisiología , Glomerulonefritis/prevención & control , Glomerulonefritis/fisiopatología , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas Mitocondriales/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Obesidad/complicaciones , Animales , Apoptosis , Supervivencia Celular , Células Cultivadas , Modelos Animales de Enfermedad , Glomerulonefritis/patología , Humanos , Inflamasomas/metabolismo , Metabolismo de los Lípidos , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Proteínas Mitocondriales/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Podocitos/metabolismo , Podocitos/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: This study aimed to evaluate the effect of oral dexamethasone in reducing kidney scars in infants with a first febrile urinary tract infection (UTI). METHODS: Children aged between 2 and 24 months with their first presumed UTI, at high risk for kidney scarring based on procalcitonin levels (≥1 ng/mL), were randomly assigned to receive dexamethasone in addition to routine care or routine care only. Kidney scars were identified by kidney scan at 6 months after initial UTI. Projections of enrollment and follow-up completion showed that the intended sample size could not be reached before funding and time to complete the study ran out. An amendment to the protocol was approved to conduct a Bayesian analysis. RESULTS: We randomized 48 children, of whom 42 had a UTI and 18 had outcome kidney scans (instead of 128 planned). Kidney scars were found in 0/7 and 2/11 patients in the treatment and control groups respectively. The probability that dexamethasone could prevent kidney scarring was 99% in the setting of an informative prior probability distribution (which fully incorporated in the final inference the information on treatment effect provided by previous studies) and 98% in the low-informative scenario (which discounted the prior literature information by 50%). The probabilities that dexamethasone could reduce kidney scar formation by up to 20% were 61% and 53% in the informative and low-informative scenario, respectively. CONCLUSIONS: Dexamethasone is highly likely to reduce kidney scarring, with a more than 50% probability to reduce kidney scars by up to 20%. TRIAL REGISTRATION NUMBER: EudraCT number: 2013-000388-10; registered in 2013 (prospectively registered) A higher resolution version of the Graphical abstract is available as Supplementary information.
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Dexametasona , Fiebre , Glomerulonefritis , Infecciones Urinarias , Administración Oral , Teorema de Bayes , Preescolar , Dexametasona/administración & dosificación , Fiebre/tratamiento farmacológico , Glomerulonefritis/prevención & control , Humanos , Lactante , Tamaño de la Muestra , Resultado del Tratamiento , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
BACKGROUND: Acute pyelonephritis in children may result in permanent kidney scarring that is primarily caused by inflammation during acute infection. Antibiotic therapy alone is not enough to significantly reduce kidney scarring, and adjuvant corticosteroid therapy has shown a significant reduction in inflammatory cytokines in urine prompting its evaluation in randomised controlled trials. A few clinical trials showed a trend towards a reduction in renal scarring but did not have an adequate sample size to show a significant effect. Therefore, we planned to synthesise the available evidence on the role of corticosteroids as adjuvant therapy in reducing kidney scarring. OBJECTIVE: To assess the efficacy and safety of adjuvant corticosteroid therapy for the prevention of kidney scarring in children with acute pyelonephritis. DESIGN: Systematic review and meta-analysis. SETTING: Community-acquired febrile urinary tract infections. PATIENTS: Children (less than 18 years) with acute pyelonephritis. INTERVENTION: Adjuvant corticosteroid therapy (along with antibiotic treatment). MAIN OUTCOME MEASURES: Primary: efficacy in preventing kidney scarring; secondary: serious adverse events associated with corticosteroid therapy. RESULTS: Three randomised trials (529 children) were included. Corticosteroids are effective in lowering the risk of kidney scarring as compared with placebo (risk ratio (RR): 0.57; 95% CI 0.36 to 0.90). No significant increase risk of bacteraemia (RR: 1.38; 95% CI 0.23 to 8.23) and hospitalisation (RR: 0.87; 95% CI 0.3 to 2.55) was observed in corticosteroid group. CONCLUSION: Moderate quality evidence suggests that short duration 'adjuvant corticosteroid therapy' along with routine antibiotic therapy in acute febrile urinary tract infection significantly reduces the risk of kidney scarring without any significant adverse effects.
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Corticoesteroides/uso terapéutico , Glomerulonefritis/prevención & control , Riñón/patología , Pielonefritis/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Corticoesteroides/efectos adversos , Antibacterianos/uso terapéutico , Estudios de Casos y Controles , Quimioterapia Adyuvante/métodos , Niño , Infecciones Comunitarias Adquiridas/diagnóstico , Citocinas/efectos de los fármacos , Citocinas/orina , Quimioterapia Combinada , Femenino , Glomerulonefritis/etiología , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Masculino , Placebos/administración & dosificación , Pielonefritis/complicaciones , Pielonefritis/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Conducta de Reducción del Riesgo , Seguridad , Resultado del Tratamiento , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
BACKGROUND: Transplant glomerulopathy (TG) is a pathological feature of chronic active antibody-mediated rejection (cAMR) and is associated with renal allograft failure. The specific role of B cells in the pathogenesis of TG is unclear. METHODS: We used a minor mismatched rat kidney transplant model with B cell-deficient recipients, generated by clustered regularly interspaced short palindromic repeats/Cas9 technology, to investigate the impact of B-cell depletion on the pathogenesis of TG. We hypothesized that B-cell deficiency would prevent TG in the rat kidney transplant model of cAMR. Treatment groups included syngeneic, allogeneic, sensitized allogeneic, and B cell-deficient allogeneic transplant recipients. RESULTS: B cell-deficient recipients demonstrated reduced TG lesions, decreased microvascular inflammation, reduced allograft infiltrating macrophages, and reduced interferon gamma transcripts within the allograft. Allograft transcript levels of interferon gamma, monocyte chemoattractant protein-1, and interleukin-1ß correlated with numbers of intragraft macrophages. B cell-deficient recipients lacked circulating donor-specific antibodies and had an increased splenic regulatory T-cell population. CONCLUSIONS: In this model of cAMR, B-cell depletion attenuated the development of TG with effects on T cell and innate immunity.
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Linfocitos B/inmunología , Glomerulonefritis/prevención & control , Rechazo de Injerto/prevención & control , Isoanticuerpos/sangre , Riñón/inmunología , Animales , Linfocitos B/metabolismo , Proliferación Celular , Células Cultivadas , Enfermedad Crónica , Técnicas de Cocultivo , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Inmunidad Celular , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Riñón/metabolismo , Riñón/patología , Activación de Linfocitos , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Ratas Transgénicas , Bazo/inmunología , Bazo/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.
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Lesión Renal Aguda/tratamiento farmacológico , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glomerulonefritis/prevención & control , Hipertensión/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Piperidinas/farmacología , Daño por Reperfusión/tratamiento farmacológico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Antihipertensivos/toxicidad , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Enalapril/farmacología , Inhibidores Enzimáticos/toxicidad , Epóxido Hidrolasas/antagonistas & inhibidores , Fibrosis , Mesangio Glomerular/efectos de los fármacos , Mesangio Glomerular/patología , Mesangio Glomerular/fisiopatología , Glomerulonefritis/etiología , Glomerulonefritis/patología , Glomerulonefritis/fisiopatología , Hipertensión/etiología , Hipertensión/fisiopatología , Masculino , Ratones , Compuestos de Fenilurea/toxicidad , Piperidinas/toxicidad , Daño por Reperfusión/complicaciones , Daño por Reperfusión/fisiopatologíaRESUMEN
(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active ß-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active ß-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the ß-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/ß-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.
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Proliferación Celular , Glomerulonefritis/enzimología , Células Mesangiales/enzimología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Receptores de Superficie Celular/metabolismo , Vía de Señalización Wnt , Amidas/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Fumaratos/farmacología , Glomerulonefritis/patología , Glomerulonefritis/prevención & control , Masculino , Células Mesangiales/efectos de los fármacos , Células Mesangiales/patología , Fosforilación , Ratas Endogámicas WKY , ATPasas de Translocación de Protón Vacuolares , Vía de Señalización Wnt/efectos de los fármacos , Proteína Wnt4/metabolismo , beta Catenina/metabolismoRESUMEN
Astragaloside IV(AS-IV), a saponin purified from Astragalus membranaceus (Fisch.) Bge.var.mongholicus (Bge.) Hsiao, has been widely used in traditional Chinese medicine. However, the underlying mechanisms in treating chronic glomerular nephritis (CGN) have not been fully understood. The aim of the present study was to evaluate the potential mechanism of AS-IV on CGN. CGN rats were administrated with AS-IV at 10 mg·kg-1 ·d-1 (ASL) and 20 mg·kg-1 ·d-1 (ASH). Twenty four hour proteinuria, blood urea nitrogen (BUN), and serum creatinine (SCr) were detected. Hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining were performed to evaluate the kidney lesion. Transmission electron microscope and GFP-RFP-LC3 transfection assay were used to monitor the effect of AS-IV on autophagy. IL-6 and IL-1ß were detected. The expression of CyclinD1, PI3K/AKT/AS160 pathway and autophagy related proteins were detected by Western Blot. The results demonstrated that AS-IV improved kidney function, ameliorated kidney lesion, and diminished inflammatory in CGN rats. Further, both in vivo and vitro study demonstrated that AS-IV inhibited the proliferation of mesangial cells. AS-IV further displayed a remarkable effect on inhibiting the activation of PI3K/AKT/AS160 pathway and improved the activation of autophagy in vivo and vitro. These results suggested that AS-IV is a potential therapeutic agent for CGN and merits further investigation.
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Autofagia/efectos de los fármacos , Glomerulonefritis/prevención & control , Insuficiencia Renal Crónica/prevención & control , Saponinas/farmacología , Triterpenos/farmacología , Animales , Astragalus propinquus/química , Células Cultivadas , Citoprotección/efectos de los fármacos , Proteínas Activadoras de GTPasa/metabolismo , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/patología , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: To evaluate the efficacy of adjuvant systemic corticosteroids in reducing kidney scarring. A previous study suggested that use of adjuvant systemic corticosteroids reduces kidney scarring in children radiologically confirmed to have extensive pyelonephritis. Efficacy of corticosteroids for children with febrile urinary tract infection (UTI) has not been studied. METHODS: Children aged 2 months to 6 years with their first febrile UTI were randomized to corticosteroids or placebo for 3 days (both arms received antimicrobial therapy); kidney scarring was assessed using 99mTc-dimercaptosuccinic acid kidney scan 5-24 months after the initial UTI. RESULTS: We randomized 546 children of which 385 had a UTI and 254 had outcome kidney scans (instead of the 320 planned). Rates of kidney scarring were 9.8% (12/123) and 16.8% (22/131) in the corticosteroid and placebo groups, respectively (p = 0.16), corresponding to an absolute risk reduction of 5.9% (95% confidence interval: - 2.2, 14.1). CONCLUSION: While children randomized to adjuvant corticosteroids tended to develop fewer kidney scars than children who were randomized to receive placebo, a statistically significant difference was not achieved. However, the study was limited by not reaching its intended sample size. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov , NCT01391793, Registered 7/12/2011 Graphical abstract.
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Corticoesteroides/administración & dosificación , Glomerulonefritis/prevención & control , Infecciones Urinarias/tratamiento farmacológico , Adyuvantes Farmacéuticos/administración & dosificación , Adyuvantes Farmacéuticos/efectos adversos , Corticoesteroides/efectos adversos , Factores de Edad , Antibacterianos/uso terapéutico , Preescolar , Método Doble Ciego , Femenino , Fiebre , Glomerulonefritis/diagnóstico por imagen , Humanos , Lactante , MasculinoRESUMEN
Human parvovirus B19 has been associated with various cases of kidney injuries with different glomerular phenotypes. In immunocompromised individuals, insufficient production of neutralizing antibodies can lead to chronic PVB19 carriage and manifestations. However, PVB19 DNA has been detected in bone marrow and peripheral blood for months or years in seemingly immunocompetent individuals, despite the presence of neutralizing antibodies. We report here PVB19-induced recurrent anuric acute kidney failures in a 57-year-old man over a 7-year period with persistent PVB19 infection and then PVB19-associated cryoglobulinemia. Acute renal failures were preceded by influenza-like syndrome associated with arthralgia, skin rash, and low-grade fever. Serum, bone marrow, renal, and digestive PVB19 replication was found in the different episodes. Endocapillary proliferative glomerulonephritis evolved into membranoproliferative glomerulonephritis. Complete renal recovery occurred after each bout. Off-label subcutaneous immunoglobulin therapy resulted in disappearance of blood and bone marrow PVB19 viral load and stopped the glomerulonephritis recurrence. Subcutaneous immunoglobulin therapy withdrawal resulted in renal relapse with cryoglobulin-associated manifestations.
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Lesión Renal Aguda/prevención & control , Inmunoglobulinas/administración & dosificación , Infecciones por Parvoviridae/prevención & control , Parvovirus B19 Humano/aislamiento & purificación , Lesión Renal Aguda/virología , Crioglobulinemia/prevención & control , Crioglobulinemia/virología , ADN Viral/análisis , Glomerulonefritis/prevención & control , Glomerulonefritis/virología , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Uso Fuera de lo Indicado , Infecciones por Parvoviridae/virología , Recurrencia , Carga ViralRESUMEN
BACKGROUND: Direct-acting anti-viral (DAA) therapy may have a beneficial role in extrahepatic manifestations of hepatitis C virus (HCV) infection. However, the available data are limited. AIM: To examine the effects of DAA treatment on the risk of several extrahepatic manifestations of HCV. METHODS: We conducted a retrospective cohort study of patients from the US Department of Veterans Affairs Corporate Data Warehouse who had a positive HCV RNA test and received first course of DAAs between 2012 and 2016. We calculated incidence rates by sustained virological response (SVR) status for six extrahepatic manifestations, and effect of SVR on these conditions was evaluated in adjusted Cox regression models. RESULTS: Of the 45 260 patients treated with DAA with mean follow-up of 2.01 years, 41 711 (92.2%) experienced SVR. Incidence rates ranged from 0.17/1000 PY for porphyria cutanea tarda to 21.04/1000 PY for diabetes in the SVR group and 0.51/1000 PY for porphyria cutanea tarda to 23.11/1000 PY for diabetes in the no SVR group. The risk was reduced with SVR for mixed cryoglobulinaemia (adjusted HR (aHR) = 0.23; 95% CI 0.10-0.56), glomerulonephritis (aHR = 0.61; 95% CI 0.41-0.90) and lichen planus (aHR = 0.46; 95% CI 0.30-0.70), but not for non-Hodgkin's lymphoma (aHR = 0.86; 95% CI 0.52-1.43) or diabetes (aHR = 0.98; 95% CI 0.81-1.19). Non significant risk reduction was seen for porphyria cutanea tarda (aHR = 0.33; 95% CI 0.11-1.03). CONCLUSIONS: Successful DAA treatment resulting in SVR was associated with significant reductions in the risk of mixed cryoglobulinaemia, glomerulonephritis, lichen planus and possibly porphyria cutanea tarda, but not non-Hodgkin's lymphoma or diabetes.
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Antivirales/uso terapéutico , Crioglobulinemia/prevención & control , Glomerulonefritis/prevención & control , Hepatitis C/tratamiento farmacológico , Liquen Plano/prevención & control , Porfiria Cutánea Tardía/prevención & control , Respuesta Virológica Sostenida , Crioglobulinemia/etiología , Femenino , Glomerulonefritis/etiología , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C/complicaciones , Hepatitis C/virología , Humanos , Liquen Plano/etiología , Masculino , Persona de Mediana Edad , Porfiria Cutánea Tardía/etiología , Estudios Retrospectivos , RiesgoRESUMEN
Obesity, metabolic syndrome, and renal injury are considered risk factors for type 2 diabetes, as well as kidney disease. Functional and structural changes in the kidney as consequence of obesity and metabolic syndrome may lead to impaired mineral metabolism in what is known as chronic kidney disease-mineral and bone disorder. Lifestyle interventions such as physical activity are good strategies to manage these pathologies and therefore, prevent the loss of kidney functionality and related complications in mineral metabolism. In this study, we have used 40 male Zucker rats that were randomly allocated into four different experimental groups, two of them (an obese and a lean one) performed an aerobic interval training protocol, and the other two groups were sedentary. At the end of the experimental period (8 wk), urine, plasma, and femur were collected for biochemical and mineral composition analysis, whereas the kidney was processed for histological studies. The obese rats exhibited albuminuria, glomerulosclerosis, and hypertrophy in glomeruli and renal tubule in some areas, together with alterations in mineral content of plasma but not of femur. The training protocol prevented the generation of albuminuria and glomerulosclerosis, showing a significant action on plasma and bone mineral levels. Therefore, the specific training protocol used in this study was able to prevent the development of diabetic nephropathy and affected the metabolism of certain minerals.
Asunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/prevención & control , Fémur/metabolismo , Glomerulonefritis/prevención & control , Entrenamiento de Intervalos de Alta Intensidad , Riñón/fisiopatología , Minerales/sangre , Obesidad/terapia , Albuminuria/etiología , Albuminuria/metabolismo , Albuminuria/fisiopatología , Albuminuria/prevención & control , Animales , Biomarcadores/sangre , Biomarcadores/orina , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Modelos Animales de Enfermedad , Glomerulonefritis/etiología , Glomerulonefritis/metabolismo , Glomerulonefritis/fisiopatología , Hipertrofia , Riñón/patología , Masculino , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/fisiopatología , Ratas Zucker , Recuperación de la Función , Factores de TiempoRESUMEN
Prostaglandin E2 (PGE2) signaling is known to modulate inflammation and vascular resistance. Receptors of PGE2 [E-type prostanoid receptors (EP)] might be an attractive pharmacological target in immune-mediated diseases such as glomerulonephritis. We hypothesized that selective EP4 antagonism improves nephrotoxic serum nephritis (NTS) by its anti-inflammatory properties. Mice were subjected to NTS and treated with the EP4 antagonist ONO AE3-208 (10 mg·kg body wt-1·day-1] or vehicle starting from disease initiation. In one set of experiments, treatment was started 4 days after NTS induction. Tubular epithelial cells were evaluated in vitro under starving conditions. EP4 antagonist treatment significantly improved the NTS phenotype without affecting blood pressure levels. Remarkably, the improved NTS phenotype was also observed when treatment was started 4 days after NTS induction. EP4 antagonism decreased tubular chemokine (C-X-C motif) ligand ( Cxcl) 1 and Cxcl-5 expression and thereby subsequently reduced interstitial neutrophil infiltration into the kidney. In vitro, tubular epithelial cells increasingly expressed Cxcl-5 mRNA and Cxcl-5 protein when treated with PGE2 or an EP4 agonist under starving conditions, which was blunted by EP4 antagonist treatment. Together, EP4 antagonism improves the NTS phenotype, probably by decreasing mainly Cxcl-5 production in tubular cells, thereby reducing renal neutrophil infiltration.
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Antiinflamatorios/farmacología , Glomerulonefritis/prevención & control , Túbulos Renales/efectos de los fármacos , Naftalenos/farmacología , Fenilbutiratos/farmacología , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Línea Celular , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL5/genética , Quimiocina CXCL5/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Glomerulonefritis/sangre , Glomerulonefritis/inmunología , Interleucina-6/genética , Interleucina-6/metabolismo , Túbulos Renales/inmunología , Túbulos Renales/metabolismo , Masculino , Ratones Endogámicos C57BL , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Fenotipo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Autophagy has been identified as a cellular process of bulk degradation of cytoplasmic components and its persistent activation is critically involved in the renal damage induced by ureteral obstruction. However, the role and underlying mechanisms of autophagy in hyperuricemic nephropathy (HN) remain unknown. In the present study, we observed that inhibition of autophagy by 3-methyladenine (3-MA) abolished uric acid-induced differentiation of renal fibroblasts to myofibroblasts and activation of transforming growth factor-ß1 (TGF-ß1), epidermal growth factor receptor (EGFR), and Wnt signaling pathways in cultured renal interstitial fibroblasts. Treatment with 3-MA also abrogated the development of HN in vivo as evidenced by improving renal function, preserving renal tissue architecture, reducing the number of autophagic vacuoles, and decreasing microalbuminuria. Moreover, 3-MA was effective in attenuating renal deposition of extracellular matrix (ECM) proteins and expression of α-smooth muscle actin (α-SMA) and reducing renal epithelial cells arrested at the G2/M phase of cell cycle. Injury to the kidney resulted in increased expression of TGF-ß1 and TGFß receptor I, phosphorylation of Smad3 and TGF-ß-activated kinase 1 (TAK1), and activation of multiple cell signaling pathways associated with renal fibrogenesis, including Wnt, Notch, EGFR, and nuclear factor-κB (NF-κB). 3-MA treatment remarkably inhibited all these responses. In addition, 3-MA effectively suppressed infiltration of macrophages and lymphocytes as well as release of multiple profibrogenic cytokines/chemokines in the injured kidney. Collectively, these findings indicate that hyperuricemia-induced autophagy is critically involved in the activation of renal fibroblasts and development of renal fibrosis and suggest that inhibition of autophagy may represent a potential therapeutic strategy for HN.
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Adenina/análogos & derivados , Autofagia/efectos de los fármacos , Glomerulonefritis/prevención & control , Hiperuricemia/tratamiento farmacológico , Riñón/efectos de los fármacos , Miofibroblastos/efectos de los fármacos , Adenina/farmacología , Animales , Proteínas Relacionadas con la Autofagia/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Fibrosis , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Hiperuricemia/metabolismo , Hiperuricemia/patología , Riñón/metabolismo , Riñón/ultraestructura , Masculino , Miofibroblastos/metabolismo , Miofibroblastos/ultraestructura , Estrés Oxidativo/efectos de los fármacos , Fenotipo , Fosforilación , Ratas , Ratas Sprague-Dawley , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Ectopic lymphoid structures (ELS) consist of B-cell and T-cell aggregates that are initiated de novo in inflamed tissues outside of secondary lymphoid organs. When organized within follicular dendritic cell (FDC) networks, ELS contain functional germinal centers that can yield autoantibody-secreting plasma cells and promote autoimmune disease. Intranasal instillation of lupus-prone mice with crystalline silica (cSiO2), a respirable particle linked to human lupus, triggers ELS formation in the lung, systemic autoantibodies, and early onset of glomerulonephritis. Here we tested the hypothesis that consumption of docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid with anti-inflammatory properties, influences the temporal profile of cSiO2-induced pulmonary ectopic germinal center formation and development of glomerulonephritis. Female NZBWF1 mice (6-wk old) were fed purified isocaloric diets supplemented with 0, 4, or 10 g/kg DHA - calorically equivalent to 0, 2, or 5 g DHA per day consumption by humans, respectively. Beginning at age 8 wk, mice were intranasally instilled with 1 mg cSiO2, or saline vehicle alone, once per wk, for 4 wk. Cohorts were sacrificed 1, 5, 9, or 13 wk post-instillation (PI) of the last cSiO2 dose, and lung and kidney lesions were investigated by histopathology. Tissue fatty acid analyses confirmed uniform dose-dependent DHA incorporation across all cohorts. As early as 1 wk PI, inflammation comprising of B (CD45R+) and T (CD3+) cell accumulation was observed in lungs of cSiO2-treated mice compared to vehicle controls; these responses intensified over time. Marked follicular dendritic cell (FDC; CD21+/CD35+) networking appeared at 9 and 13 wk PI. IgG+ plasma cells suggestive of mature germinal centers were evident at 13 wk. DHA supplementation dramatically suppressed cSiO2-triggered B-cell, T-cell, FDC, and IgG+ plasma cell appearance in the lungs as well as anti-dsDNA IgG in bronchial lavage fluid and plasma over the course of the experiment. cSiO2 induced glomerulonephritis with concomitant B-cell accumulation in the renal cortex at 13 wk PI but this response was abrogated by DHA feeding. Taken together, realistic dietary DHA supplementation prevented initiation and/or progression of ectopic lymphoid neogenesis, germinal center development, systemic autoantibody elevation, and resultant glomerulonephritis in this unique preclinical model of environment-triggered lupus.
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Suplementos Dietéticos , Ácidos Docosahexaenoicos/farmacología , Centro Germinal , Glomerulonefritis , Pulmón , Lupus Eritematoso Sistémico , Dióxido de Silicio/toxicidad , Animales , Femenino , Centro Germinal/inmunología , Centro Germinal/patología , Glomerulonefritis/inducido químicamente , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Glomerulonefritis/prevención & control , Pulmón/inmunología , Pulmón/patología , Lupus Eritematoso Sistémico/inducido químicamente , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Lupus Eritematoso Sistémico/prevención & control , RatonesRESUMEN
Oxidative stress, inflammation, and hyperglycemia are considered to play crucial roles in the pathogenesis and progression of diabetic nephropathy (DN). Liquiritigenin, one of the flavonoid compounds, has been shown to possess anti-inflammatory, anti-hyperlipidemic, and anti-oxidative properties. Our study aimed to explore the effects of liquiritigenin on high glucose (HG)-induced extracellular matrix (ECM) accumulation, oxidative stress and inflammatory response and delineate the underlying mechanism. In our study, glomerular mesangial cells (HBZY-1) were co-treated with various doses of liquiritigenin and HG. We found that HG, but not normal glucose or mannitol, promoted the proliferation of HBZY-1 cells, which was suppressed by liquiritigenin. Liquiritigenin inhibited HG-induced ECM accumulation in HBZY-1 cells by reducing the expressions and production of collagen IV (Col IV) and fibronectin (FN). Moreover, liquiritigenin attenuated HG-induced oxidative stress, as evidenced by the decreased MDA content and NADPH oxidase 4 (NOX4) expression, and the increased SOD activity in HBZY-1 cells. Liquiritigenin suppressed HG-induced inflammatory response, as demonstrated by the reduced expressions and secretion of interleukin (IL)-6 and IL-1ß in HBZY-1 cells. Furthermore, we found that liquiritigenin inhibited HG-induced activation the nuclear factor-kappa B (NF-κB) and nod-like receptor protein 3 (NLRP3) inflammasome pathways. In conclusion, these results demonstrated that liquiritigenin attenuated HG-induced ECM accumulation, oxidative stress, and inflammation by suppression of the NF-κB and NLRP3 inflammasome pathways, suggesting that liquiritigenin might be a promising therapeutic agent for preventing the development of DN.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Nefropatías Diabéticas/prevención & control , Matriz Extracelular/efectos de los fármacos , Flavanonas/farmacología , Glomerulonefritis/prevención & control , Glucosa/toxicidad , Inflamasomas/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Células Mesangiales/efectos de los fármacos , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Citoprotección , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Relación Dosis-Respuesta a Droga , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Inflamasomas/inmunología , Inflamasomas/metabolismo , Células Mesangiales/inmunología , Células Mesangiales/metabolismo , Células Mesangiales/patología , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Previous studies by us and others have indicated that renal epidermal growth factor receptors (EGFR) are activated in models of diabetic nephropathy (DN) and that inhibition of EGFR activity protects against progressive DN in type 1 diabetes. In this study we examined whether inhibition of EGFR activation would affect the development of DN in a mouse model of accelerated type 2 diabetes (BKS db/db with endothelial nitric oxide knockout [eNOS-/-db/db]). eNOS-/-db/db mice received vehicle or erlotinib, an inhibitor of EGFR tyrosine kinase activity, beginning at 8 weeks of age and were sacrificed at 20 weeks of age. In addition, genetic models inhibiting EGFR activity (waved 2) and transforming growth factor-α (waved 1) were studied in this model of DN in type 2 diabetes. Compared with vehicle-treated mice, erlotinib-treated animals had less albuminuria and glomerulosclerosis, less podocyte loss, and smaller amounts of renal profibrotic and fibrotic components. Erlotinib treatment decreased renal oxidative stress, macrophage and T-lymphocyte infiltration, and the production of proinflammatory cytokines. Erlotinib treatment also preserved pancreas function, and these mice had higher blood insulin levels at 20 weeks, decreased basal blood glucose levels, increased glucose tolerance and insulin sensitivity, and increased blood levels of adiponectin compared with vehicle-treated mice. Similar to the aforementioned results, both waved 1 and waved 2 diabetic mice also had attenuated DN, preserved pancreas function, and decreased basal blood glucose levels. In this mouse model of accelerated DN, inhibition of EGFR signaling led to increased longevity.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/uso terapéutico , Resistencia a la Insulina , Moduladores del Transporte de Membrana/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Albuminuria/etiología , Albuminuria/prevención & control , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Biomarcadores/orina , Cruzamientos Genéticos , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/fisiopatología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Fibrosis , Glomerulonefritis/inmunología , Glomerulonefritis/fisiopatología , Glomerulonefritis/prevención & control , Hipoglucemiantes/uso terapéutico , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Ratones Noqueados , Ratones Mutantes , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Factor de Crecimiento Transformador alfa/genética , Factor de Crecimiento Transformador alfa/metabolismoRESUMEN
BACKGROUND: Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase extensively implicated in diseases such as cancer, atherosclerosis and fibrosis. Multiple preclinical studies, performed using either a gene deletion or a gene silencing approaches, have shown this receptor being a major driver target of fibrosis and glomerulosclerosis. METHODS: The present study investigated the role and relevance of DDR1 in human crescentic glomerulonephritis (GN). Detailed DDR1 expression was first characterized in detail in human GN biopsies using a novel selective anti-DDR1 antibody using immunohistochemistry. Subsequently the protective role of DDR1 was investigated using a highly selective, novel, small molecule inhibitor in a nephrotoxic serum (NTS) GN model in a prophylactic regime and in the NEP25 GN mouse model using a therapeutic intervention regime. RESULTS: DDR1 expression was shown to be mainly limited to renal epithelium. In humans, DDR1 is highly induced in injured podocytes, in bridging cells expressing both parietal epithelial cell (PEC) and podocyte markers and in a subset of PECs forming the cellular crescents in human GN. Pharmacological inhibition of DDR1 in NTS improved both renal function and histological parameters. These results, obtained using a prophylactic regime, were confirmed in the NEP25 GN mouse model using a therapeutic intervention regime. Gene expression analysis of NTS showed that pharmacological blockade of DDR1 specifically reverted fibrotic and inflammatory gene networks and modulated expression of the glomerular cell gene signature, further validating DDR1 as a major mediator of cell fate in podocytes and PECs. CONCLUSIONS: Together, these results suggest that DDR1 inhibition might be an attractive and promising pharmacological intervention for the treatment of GN, predominantly by targeting the renal epithelium.