RESUMEN
In the present study, we investigated whether curcumin administration would interfere with the main renal features of l-NAME-induced hypertension model. For this purpose, we conducted both in vitro and in vivo experiments to evaluate renal indicators of inflammation, oxidative stress, and metalloproteinases (MMPs) expression/activity. Hypertension was induced by l-NAME (70 mg/kg/day), and Wistar rats from both control and hypertensive groups were treated with curcumin (50 or 100 mg/kg/day; gavage) or vehicle for 14 days. Blood and kidneys were collected to determine serum creatinine levels, histological alterations, oxidative stress, MMPs expression and activity, and ED1 expression. l-NAME increased blood pressure, but both doses of curcumin treatment reduced these values. l-NAME treatment increased creatinine levels, glomeruli area, Bowman's space, kidney MMP-2 activity, as well as MMP-9 and ED1 expression, and reduced the number of glomeruli. Curcumin treatment prevented the increase in creatinine levels, MMP-2 activity, and reduced MMP-2, MMP-9, ED1, and superoxide levels, as well as increased superoxide dismutase activity and partially prevented glomeruli alterations. Moreover, curcumin directly inhibited MMP-2 activity in vitro. Thus, our main findings demonstrate that curcumin reduced l-NAME-induced hypertension and renal glomerular alterations, inhibited MMP-2 and MMP-9 expression/activity, and reduced oxidative stress and inflammatory processes, which may indirectly impact hypertension-induced renal outcomes.
Asunto(s)
Curcumina , Hipertensión , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , NG-Nitroarginina Metil Éster , Ratas Wistar , Animales , Curcumina/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Ratas , Masculino , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Estrés Oxidativo/efectos de los fármacos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/tratamiento farmacológicoRESUMEN
BACKGROUND: Data monitoring and surveillance systems are the cornerstone for governance and regulation, planning, and policy development for chronic disease care. Our study aims to evaluate health systems capacity for data monitoring and surveillance for kidney care. METHODS: We leveraged data from the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA), an international survey of stakeholders (clinicians, policymakers and patient advocates) from 167 countries conducted between July and September 2022. ISN-GKHA contains data on availability and types of kidney registries, the spectrum of their coverage, as well as data on national policies for kidney disease identification. RESULTS: Overall, 167 countries responded to the survey, representing 97.4% of the global population. Information systems in forms of registries for dialysis care were available in 63% (n = 102/162) of countries, followed by kidney transplant registries (58%; n = 94/162), and registries for non-dialysis chronic kidney disease (19%; n = 31/162) and acute kidney injury (9%; n = 14/162). Participation in dialysis registries was mandatory in 57% (n = 58) of countries; however, in more than half of countries in Africa (58%; n = 7), Eastern and Central Europe (67%; n = 10), and South Asia (100%; n = 2), participation was voluntary. The least-reported performance measures in dialysis registries were hospitalization (36%; n = 37) and quality of life (24%; n = 24). CONCLUSIONS: The variability of health information systems and early identification systems for kidney disease across countries and world regions warrants a global framework for prioritizing the development of these systems.
Asunto(s)
Salud Global , Enfermedades Renales , Sistema de Registros , Humanos , Sistema de Registros/estadística & datos numéricos , Enfermedades Renales/diagnóstico , Enfermedades Renales/terapia , Enfermedades Renales/epidemiología , Diagnóstico PrecozRESUMEN
PURPOSE: The purpose of this study was to assess the bladder and renal functional outcomes of holmium laser enucleation of the prostate (HoLEP) in patients with benign prostatic obstruction (BPO) complicated by detrusor underactivity (DU) and secondary renal dysfunction. METHODS: Thirty-one patients were included in this prospective study. Eligible patients had urinary retention, a bladder outlet obstruction index (BOOI) greater than 40, a bladder contractility index (BCI) less than 100, abnormal renal function at the initial diagnosis (serum creatinine > 132 µmol/L) and a renal pelvis anteroposterior diameter (PRAPD) > 1.5 cm bilaterally. All patients underwent HoLEP in a routine manner and were evaluated preoperatively and at 1, 3 and 6 months after surgery. The baseline characteristics of the patients, perioperative data, postoperative outcomes and complications were assessed. RESULTS: Significant improvement was observed in the international prostate symptom score (IPSS), quality of life (QoL) score, maximal urinary flow rate (Qmax), post-void residual volume (PVR), Scr and RPAPD at the 6-month follow-up. Bladder wall thickness (BWT) exhibited a decreasing trend but did not significantly differ from the preoperative values. No grade 3 or higher adverse events occurred, and grade 3 and lower complications were treated conservatively. Three patients required reinsertion of indwelling catheters, and they were able to void spontaneously after two weeks of catheterisation training and medication treatment. CONCLUSION: HoLEP is an effective treatment for men with BPO accompanied by DU and consequent renal function impairment. Patients are able to regain spontaneous voiding. Both bladder and renal functions were preserved and improved.
Asunto(s)
Láseres de Estado Sólido , Hiperplasia Prostática , Obstrucción del Cuello de la Vejiga Urinaria , Vejiga Urinaria de Baja Actividad , Humanos , Masculino , Láseres de Estado Sólido/uso terapéutico , Anciano , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/cirugía , Vejiga Urinaria de Baja Actividad/fisiopatología , Estudios Prospectivos , Persona de Mediana Edad , Obstrucción del Cuello de la Vejiga Urinaria/cirugía , Obstrucción del Cuello de la Vejiga Urinaria/etiología , Resultado del Tratamiento , Terapia por Láser/métodos , Prostatectomía/métodos , Prostatectomía/efectos adversos , Enfermedades Renales/cirugía , Enfermedades Renales/complicacionesRESUMEN
Successful kidney transplant corrects mineral and bone disorderto a large extent; however, disorders can persistin up to 80% ofrecipients.We describe a case of persistent hyperparathyroidism with graft dysfunction and metastatic calcification in graft biopsy. A 48-yearold renal transplant recipient developed graft dysfunction 3 weeks after kidney transplant. During pretransplant workup, the recipient was found to have severe secondary hyperparathyroidism (intact parathyroid hormone level of 2000 pg/mL), which was managed and well controlled before transplant. Graft dysfunction was evaluated using algorithmic approach. Prerenal causes, tacrolimus toxicity, and infections were ruled out. Graft biopsy revealed several foci of tubular and parenchyma calcific deposits (microcalcinosis) with tubular injury. The patient was restarted on medical management of hyperparathyroidism, and he showed improvement over 6 weeks, along with creatinine level returning to nadir value. Vascular and graft calcification is an independent predictor of long-term graftfunction and overall mortality. This report describes the challenges that we faced in diagnosis and management of persistent hyperparathyroidism, as no randomized controlled trials and guidelines are available.
Asunto(s)
Calcinosis , Hiperparatiroidismo Secundario , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/diagnóstico , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Biopsia , Calcinosis/etiología , Calcinosis/cirugía , Calcinosis/diagnóstico , Aloinjertos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Biomarcadores/sangre , Factores de Tiempo , Enfermedades Renales/etiología , Enfermedades Renales/diagnóstico , Hormona ParatiroideaRESUMEN
A 10-year-old spayed female mixed-breed dog was brought to the Ohio State University Veterinary Medical Center because of a suspected mass located to the right kidney. The mass was diagnosed by abdominal ultrasound following a recurrent lower urinary tract infection. Abdominal computed tomography revealed 2 isoattenuating, peripherally hypoattenuating, and centrally non-contrast-enhancing nodules in the right kidney; the larger one measured 1.9 cm. Initial attempts at fine-needle aspiration were unsuccessful. The dog was returned and the mass was aspirated using ultrasound guidance under heavy sedation. Cytology confirmed the presence of septic inflammation, consistent with a renal corticomedullary abscess. The dog was administered oral enrofloxacin (15 mg/kg, q24h) after diagnosis. Ultrasound guidance was used 2 wk later, under general anesthesia, to achieve percutaneous drainage of ~0.25 mL of fluid and instillation of 5.7 mg (0.25 mL) of enrofloxacin into the abscess capsule. Two weeks after percutaneous drainage, ultrasound examination showed complete resolution of the renal corticomedullary abscess. Urine culture confirmed resolution of the urinary tract infection. To the authors' knowledge, kidney-sparing medical management has never been successfully reported in a dog with a renal corticomedullary abscess. Key clinical message: Renal corticomedullary abscesses occur infrequently in dogs. Medical management is feasible and can result in complete resolution of clinical signs and imaging abnormalities.
Diagnostic et prise en charge médicale réussie d'un abcès corticomédullaire rénal chez un chienUne chienne croisée de 10 ans, stérilisée, a été amenée au centre médical vétérinaire de l'Ohio State University en raison d'une masse suspectée située au niveau du rein droit. La masse a été diagnostiquée par échographie abdominale à la suite d'une infection récurrente du tractus urinaire inférieur. La tomodensitométrie abdominale a révélé 2 nodules isoatténuants, hypoatténuants en périphérie et centralement sans contraste dans le rein droit; le plus grand mesurait 1,9 cm. Les premières tentatives d'aspiration à l'aiguille fine ont échoué. Le chien est revenu et la masse a été aspirée sous guidage échographique sous sédation lourde. La cytologie a confirmé la présence d'une inflammation septique, compatible avec un abcès corticomédullaire rénal. Le chien a reçu de l'enrofloxacine par voie orale (15 mg/kg, toutes les 24 heures) après le diagnostic. Le guidage échographique a été utilisé 2 semaines plus tard, sous anesthésie générale, pour obtenir un drainage percutané d'environ 0,25 mL de liquide et l'instillation de 5,7 mg (0,25 mL) d'enrofloxacine dans la capsule de l'abcès. Deux semaines après le drainage percutané, l'échographie a montré une résolution complète de l'abcès corticomédullaire rénal. La culture urinaire a confirmé la résolution de l'infection des voies urinaires. À la connaissance des auteurs, une prise en charge médicale préservant les reins n'a jamais été rapportée avec succès chez un chien présentant un abcès corticomédullaire rénal.Message clinique clé:Les abcès corticomédullaires rénaux surviennent rarement chez le chien. La prise en charge médicale est réalisable et peut aboutir à une résolution complète des signes cliniques et des anomalies d'imagerie.(Traduit par Dr Serge Messier).
Asunto(s)
Absceso , Antibacterianos , Enfermedades de los Perros , Enrofloxacina , Animales , Perros , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/diagnóstico por imagen , Femenino , Absceso/veterinaria , Absceso/tratamiento farmacológico , Absceso/diagnóstico , Enrofloxacina/uso terapéutico , Enrofloxacina/administración & dosificación , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Infecciones Urinarias/veterinaria , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/diagnóstico , Enfermedades Renales/veterinaria , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/diagnóstico , Drenaje/veterinaria , Fluoroquinolonas/uso terapéutico , Fluoroquinolonas/administración & dosificación , Ultrasonografía/veterinariaRESUMEN
Background: Deposition of adipose tissue may have a promoting role in the development of diabetic complications. This study is aimed at investigating the relationship between adipose tissue thickness and risk of contrast-induced nephropathy (CIN) in patients with Type 2 diabetes mellitus (T2DM). Methods: A total of 603 T2DM patients undergoing percutaneous coronary angiography or angioplasty with suspicious or confirmed stable coronary artery disease were enrolled in this study. The thicknesses of perirenal fat (PRF), subcutaneous fat (SCF), intraperitoneal fat (IPF), and epicardial fat (ECF) were measured by color Doppler ultrasound, respectively. The association of various adipose tissues with CIN was analyzed. Results: Seventy-seven patients (12.8%) developed CIN in this cohort. Patients who developed CIN had significantly thicker PRF (13.7 ± 4.0 mm vs. 8.9 ± 3.6 mm, p < 0.001), slightly thicker IPF (p = 0.046), and similar thicknesses of SCF (p = 0.782) and ECF (p = 0.749) compared to those who did not develop CIN. Correlation analysis showed that only PRF was positively associated with postoperation maximal serum creatinine (sCr) (r = 0.18, p = 0.012), maximal absolute change in sCr (r = 0.33, p < 0.001), and maximal percentage of change in sCr (r = 0.36, p < 0.001). In receiver operating characteristic (ROC) analysis, the area under the curve (AUC) of PRF (0.809) for CIN was significantly higher than those of SCF (0.490), IPF (0.594), and ECF (0.512). Multivariate logistic regression analysis further confirmed that thickness of PRF, rather than other adipose tissues, was independently associated with the development of CIN after adjusted for confounding factors (odds ratio (OR) = 1.53, 95% CI: 1.38-1.71, p < 0.001). Conclusions: PRF is independently associated with the development of CIN in T2DM patients undergoing coronary catheterization.
Asunto(s)
Medios de Contraste , Angiografía Coronaria , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Masculino , Medios de Contraste/efectos adversos , Persona de Mediana Edad , Anciano , Angiografía Coronaria/efectos adversos , Factores de Riesgo , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Tejido Adiposo/diagnóstico por imagen , Tejido Adiposo/patología , Enfermedades Renales/inducido químicamente , Grasa Intraabdominal/diagnóstico por imagen , Cateterismo Cardíaco/efectos adversos , Creatinina/sangreRESUMEN
Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse the progression of lung or kidney fibrosis. Myofibroblasts are key to the progression and maintenance of fibrosis. We investigated features of cell adhesion necessary for monocytes to differentiate into myofibroblasts, seeking to identify pathways key to myofibroblast differentiation. Blocking antibodies against integrins α3, αM, and αMß2 de-differentiate myofibroblasts in vitro, lower the pro-fibrotic secretome of myofibroblasts, and treat lung fibrosis and inhibit kidney fibrosis in vivo. Decorin's collagen-binding peptide can be used to direct functionalized blocking antibodies (against integrins-α3, -αM, -αMß2) to both fibrotic lungs and fibrotic kidneys, reducing the dose of antibody necessary to treat fibrosis. This targeted immunotherapy blocking key integrins may be an effective therapeutic for the treatment of fibrosis.
Asunto(s)
Fibrosis , Miofibroblastos , Fibrosis Pulmonar , Miofibroblastos/metabolismo , Miofibroblastos/patología , Animales , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Humanos , Ratones , Anticuerpos Bloqueadores/farmacología , Diferenciación Celular , Integrina alfa3/metabolismo , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Riñón/patología , Riñón/metabolismoRESUMEN
Mitochondrial dysfunction is a pivotal event contributing to the development of ageing-related kidney disorders. Lon protease 1 (LONP1) has been reported to be responsible for ageing-related renal fibrosis; however, the underlying mechanism(s) of LONP1-driven kidney ageing with respect to mitochondrial disturbances remains to be further explored. The level of LONP1 was tested in the kidneys of aged humans and mice. Renal fibrosis and mitochondrial quality control were confirmed in the kidneys of aged mice. Effects of LONP1 silencing or overexpression on renal fibrosis and mitochondrial quality control were explored. In addition, N6-methyladenosine (m6A) modification and methyltransferase like 3 (METTL3) levels, the relationship between LONP1 and METTL3, and the impacts of METTL3 overexpression on mitochondrial functions were confirmed. Furthermore, the expression of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and the regulatory effects of IGF2BP2 on LONP1 were confirmed in vitro. LONP1 expression was reduced in the kidneys of aged humans and mice, accompanied by renal fibrosis and mitochondrial dysregulation. Overexpression of LONP1 alleviated renal fibrosis and maintained mitochondrial homeostasis, while silencing of LONP1 had the opposite effect. Impaired METTL3-m6A signalling contributed at least in part to ageing-induced LONP1 modification, reducing subsequent degradation in an IGF2BP2-dependent manner. Moreover, METTL3 overexpression alleviated proximal tubule cell injury, preserved mitochondrial stability, inhibited LONP1 degradation, and protected mitochondrial functions. LONP1 mediates mitochondrial function in kidney ageing and that targeting LONP1 may be a potential therapeutic strategy for improving ageing-related renal fibrosis.
Asunto(s)
Adenosina , Envejecimiento , Fibrosis , Homeostasis , Enfermedades Renales , Riñón , Metiltransferasas , Mitocondrias , Proteínas Mitocondriales , Proteínas de Unión al ARN , Mitocondrias/metabolismo , Animales , Metiltransferasas/metabolismo , Metiltransferasas/genética , Humanos , Envejecimiento/metabolismo , Ratones , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Riñón/patología , Riñón/metabolismo , Masculino , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/etiología , Enfermedades Renales/genética , Proteasas ATP-Dependientes/metabolismo , Proteasas ATP-Dependientes/genética , Transducción de Señal , Ratones Endogámicos C57BLRESUMEN
Despite significant breakthroughs in the understanding of immunological and pathophysiological features for immune-mediated kidney diseases, a proportion of patients exhibit poor responses to current therapies or have been categorized as refractory renal disease. Engineered T cells have emerged as a focal point of interest as a potential treatment strategy for kidney diseases. By genetically modifying T cells and arming them with chimeric antigen receptors (CARs), effectively targeting autoreactive immune cells, such as B cells or antibody-secreting plasma cells, has become feasible. The emergence of CAR T-cell therapy has shown promising potential in directing effector and regulatory T cells (Tregs) to the site of autoimmunity, paving the way for effective migration, proliferation, and execution of suppressive functions. Genetically modified T-cells equipped with artificial receptors have become a novel approach for alleviating autoimmune manifestations and reducing autoinflammatory events in the context of kidney diseases. Here, we review the latest developments in basic, translational, and clinical studies of CAR-based therapies for immune-mediated kidney diseases, highlighting their potential as promising avenues for therapeutic intervention.
Asunto(s)
Inmunoterapia Adoptiva , Enfermedades Renales , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Inmunoterapia Adoptiva/métodos , Enfermedades Renales/terapia , Enfermedades Renales/inmunología , Animales , Linfocitos T/inmunologíaRESUMEN
BACKGROUNDIt is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODSThree cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTSMonogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (-3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (-2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONSMonogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATIONNA.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.
Asunto(s)
Apolipoproteína L1 , Tasa de Filtración Glomerular , Insuficiencia Renal , Humanos , Masculino , Femenino , Adulto , Apolipoproteína L1/genética , Persona de Mediana Edad , Insuficiencia Renal/genética , Factores de Riesgo , Niño , Estudios Retrospectivos , Adolescente , Estudios Prospectivos , Enfermedades Renales/genéticaRESUMEN
The intersection of cardiovascular disease, metabolic disorders and chronic kidney disease represents a complex clinical picture challenging healthcare systems worldwide. Metabolic-dysfunction-associated steatotic liver disease (MASLD) often manifests sequentially or concomitantly with these diseases, and may share underlying mechanisms and risk factors. Growing evidence suggests that new therapies could have benefits across these diseases, but trial sponsors and investigators tend to be reluctant to include patients with comorbidities-particularly liver diseases-in clinical trials. In this Perspective, we call for inclusion of patients with MASLD and measurement of liver outcomes in cardio-kidney-metabolic trials, when data suggest mechanistically plausible benefits and liver and cardiovascular safety. We discuss the implications of this new paradigm for clinical trial design and considerations for regulatory approval. Finally, we outline the challenges to implementing such an approach and provide recommendations for future clinical trial conduct.
Asunto(s)
Enfermedades Cardiovasculares , Ensayos Clínicos como Asunto , Humanos , Hígado/patología , Enfermedades Renales , Hígado Graso/terapia , Insuficiencia Renal Crónica/terapiaRESUMEN
OBJECTIVE: To explore the effects of Qingshen Granules (QSG) on adenine-induced renal fibrosis in mice and in uric acid (UA)-stimulated NRK-49F cells and its mechanism for regulating exosomes, miR-330-3p and CREBBP. METHODS: A mouse model of adenine-induced renal fibrosis were treated daily with QSG at 8.0 g·kg-1·d-1 via gavage for 12 weeks. An adenoassociated virus vector was injected into the tail vein, and renal tissues of the mice were collected for analyzing exosomal marker proteins CD9, Hsp70, and TSG101 and expressions of Col-III, α-SMA, FN, and E-cad using Western blotting and immunofluorescence and for observing pathological changes using HE and Masson staining. In the cell experiment, NRK-49F cells were stimulated with uric acid (400 µmol/L) followed by treatment with QSG-medicated serum from SD rats, and the changes in expressions of the exosomal markers and Col-III, α-SMA, FN, and E-cad were analyzed. Dual luciferase reporter assay was employed to examine the targeting relationship between miR-330-3p and CREBBP, whose expressions were detected by RT-qPCR and Western blotting in treated NRK-49F cells. RESULTS: The mouse models of adenine-induced renal fibrosis showed significantly increased levels of CD9, Hsp70, and TSG101, which were decreased by treatment with QSG. The expressions of Col-III, α-SMA, and FN increased and Ecad decreased in the mouse models but these changes were reversed by QSG treatment. QSG treatment obviously alleviated renal fibrosis in the mouse models. Intravenous injection of adeno-associated viral vector obviously inhibited miR-330-3p, increased CREBBP levels, and reduced fibrosis in the mouse models. Dual luciferase assay confirmed CREBBP as a target of miR-330-3p, which was consistent with the results of the cell experiments. CONCLUSION: QSG inhibits renal fibrosis in mice by regulating the exosomes, reducing miR-330-3p levels, and increasing CREBBP expression.
Asunto(s)
Exosomas , Fibrosis , Riñón , MicroARNs , Animales , Exosomas/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Riñón/patología , Riñón/metabolismo , Proteína de Unión a CREB/metabolismo , Proteína de Unión a CREB/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/inducido químicamente , Medicamentos Herbarios Chinos/farmacología , Adenina , Ratas , Masculino , Ácido Úrico , Línea CelularRESUMEN
Peroxisome proliferator-activated receptor-alpha (PPAR-α) and its exogenous activators (fibrates) promote autophagy. However, whether the deleterious effects of PPAR-α deficiency on doxorubicin (DOX)-induced podocytopathy are associated with reduced autophagy remains to be clarified. We investigated the mechanisms of PPAR-α in DOX-induced podocytopathy and tubular injury in PPAR-α knockout (PAKO) mice and in a murine podocyte cell line. DOX-treated PAKO mice showed higher serum levels of triglycerides and non-esterified fatty acids and more severe podocytopathy than DOX-treated wild-type mice, as evidenced by higher urinary levels of proteins and podocalyxin at 3 days to 2 weeks and higher blood urea nitrogen and serum creatinine levels at 4 weeks. Additionally, there was an increased accumulation of p62, a negative autophagy marker, in the glomerular and tubular regions in DOX-treated PAKO mice at Day 9. Moreover, DOX-treated PAKO mice showed more severe glomerulosclerosis and tubular damage and lower podocalyxin expression in the kidneys than DOX-treated control mice at 4 weeks. Furthermore, DOX treatment increased p-p53, an apoptosis marker, and cleaved the caspase-3 levels and induced apoptosis, which was ameliorated by fenofibrate, a PPAR-α activator. Fenofibrate further enhanced AMPK activation and autophagy under fed and fasting conditions. Conclusively, PPAR-α deficiency enhances DOX-induced podocytopathy, glomerulosclerosis, and tubular injury, possibly by reducing autophagic activity in mouse kidneys.
Asunto(s)
Autofagia , Doxorrubicina , Ratones Noqueados , PPAR alfa , Podocitos , Animales , Podocitos/metabolismo , Podocitos/patología , Podocitos/efectos de los fármacos , Doxorrubicina/efectos adversos , PPAR alfa/metabolismo , PPAR alfa/genética , Ratones , Autofagia/efectos de los fármacos , Línea Celular , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/genética , Apoptosis/efectos de los fármacos , Fenofibrato/farmacología , MasculinoRESUMEN
Glomerular kidney diseases typically begin insidiously and can progress to end stage kidney failure. Early onset of therapy can slow down disease progression. Early diagnosis is required to ensure such timely therapy. The goal of our study was to evaluate protein biomarkers (BMs) for common nephropathies that have been described for children with Alport syndrome. Nineteen candidate BMs were determined by commercial ELISA in children with congenital anomalies of the kidneys and urogenital tract, inflammatory kidney injury, or diabetes mellitus. It is particularly essential to search for kidney disease BMs in children because they are a crucial target group that likely exhibits early disease stages and in which misleading diseases unrelated to the kidney are rare. Only minor differences in blood between affected individuals and controls were found. However, in urine, several biomarker candidates alone or in combination seemed to be promising indicators of renal injury in early disease stages. The BMs of highest sensitivity and specificity were collagen type XIII, hyaluronan-binding protein 2, and complement C4-binding protein. These proteins are unrelated to inflammation markers or to risk factors for and signs of renal failure. In conclusion, our study evaluated several strong candidates for screening for early stages of kidney diseases and can help to establish early nephroprotective regimens.
Asunto(s)
Biomarcadores , Humanos , Biomarcadores/orina , Biomarcadores/sangre , Niño , Masculino , Femenino , Preescolar , Adolescente , Diagnóstico Precoz , Enfermedades Renales/diagnóstico , Enfermedades Renales/etiología , Enfermedades Renales/sangre , Inflamación , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , LactanteRESUMEN
Acute kidney injury (AKI) and chronic kidney disease (CKD) are significant public health issues associated with a long-term increase in mortality risk, resulting from various etiologies including renal ischemia, sepsis, drug toxicity, and diabetes mellitus. Numerous preclinical models have been developed to deepen our understanding of the pathophysiological mechanisms and therapeutic approaches for kidney diseases. Among these, rodent models have proven to be powerful tools in the discovery of novel therapeutics, while the development of kidney organoids has emerged as a promising advancement in the field. This review provides a comprehensive analysis of the construction methodologies, underlying biological mechanisms, and recent therapeutic developments across different AKI and CKD models. Additionally, this review summarizes the advantages, limitations, and challenges inherent in these preclinical models, thereby contributing robust evidence to support the development of effective therapeutic strategies.