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COVID-19 , SARS-CoV-2 , COVID-19/epidemiología , China/epidemiología , Humanos , Ciudades , Pandemias , Conceptos MeteorológicosRESUMEN
A major feature of the injury sustained by the kidney during obstructive nephropathy is a profound induction of apoptosis in the tubular epithelium. In this study, we explored the central roles of mitochondria and the mechanism of the protective effect of the mitochondrial targeted peptides in tubular cell apoptosis and interstitial fibrosis during obstructive nephropathy. Unilateral ureter obstruction (UUO) was performed on rats, and the animals were randomly assigned to intravenous treatment with normal saline, rat serum albumin (RSA), or HOCl-rat serum albumin (HOCl-RSA) in the presence or absence of SS-31. A sham-operation control group was set up by left ureteral dissociation but not ligation. Compared with the control group, UUO animals displayed fibrotic abnormalities, accompanied by increased expression of collagen-I, fibronectin, α-SMA protein and mRNA in the renal interstitium. They also displayed oxidative stress, as evidenced by increased levels of HOCl-alb, TBARS, and mitochondrial reactive oxygen species (ROS) and a decrease in MnSOD activity in the renal homogenate. Damage to mitochondrial structure and functions was observed, as evidenced by a decrease in the mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and release of cytochrome C (cyto C) from the mitochondria to the cytoplasm. These changes were accompanied by activation of caspase-3, caspase-7, caspase-9, and PARP-1 and increased apoptotic cells in the proximal tubules. HOCl-RSA challenge further exacerbated the above biological effects in UUO animals, but these effects were prevented by administration of SS-31. These data suggested that accumulation of HOCl-alb may promote tubular cell apoptosis and interstitial fibrosis, probably related to mitochondrial oxidative stress and damage, and that SS-31 might contribute to apoptotic pathway suppression via scavenging of ROS in the mitochondria.
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Antioxidantes/farmacología , Nefritis/tratamiento farmacológico , Oligopéptidos/farmacología , Albúmina Sérica/administración & dosificación , Obstrucción Ureteral/tratamiento farmacológico , Actinas/genética , Actinas/metabolismo , Animales , Caspasas/genética , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibronectinas/genética , Fibronectinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Hipocloroso/química , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Ligadura , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Nefritis/genética , Nefritis/metabolismo , Nefritis/patología , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Albúmina Sérica/química , Transducción de Señal , Uréter/cirugía , Obstrucción Ureteral/genética , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patologíaRESUMEN
Oxidative stress aggravates renal fibrosis, a pathway involved in almost all forms of chronic kidney disease (CKD). However, the underlying mechanism involved in the pathogenesis of renal oxidative stress has not been completely elucidated. In this study, we explored the role and mechanism of hypochlorite-modified albumin (HOCl-alb) in mediating oxidative stress and fibrotic response in a remnant-kidney rat model. Five-sixths nephrectomy (5/6 NX) was performed on the rats and then the animals were randomly assigned to intravenous treatment with either vehicle alone, or HOCl-rat serum albumin (RSA) in the presence or absence of SS-31 (administered intraperitoneally). A sham-operation control group was set up concurrently. Compared with the control group, 5/6 NX animals displayed marked mitochondrial (mt) dysfunction, as evidenced by decrease of mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and manganese superoxide dismutase (MnSOD) activity, release of cytochrome C (Cyto C) from mitochondria to the cytoplasm, and increase of mitochondrial reactive oxygen species in renal tissues. They also displayed increased levels of HOCl-alb in both plasma and renal tissues. These changes were accompanied by accumulation of extracellular matrix, worsened proteinuria, deteriorated renal function, and a marked increase of macrophage infiltration along with up-regulation of monocyte chemoattractant protein (MCP)-1 and transforming growth factor (TGF)-ß1 expression. HOCl-alb challenge further exacerbated the above biological effects in 5/6 NX animals, but these adverse effects were prevented by administration of SS-31, a mitochondrial targeted antioxidant peptide. These data suggest that accumulation of HOCl-alb may promote renal inflammation and fibrosis, probably related to mitochondrial oxidative stress and dysfunction and that the mitochondrial targeted peptide SS-31 might be a novel therapy for renal fibrosis and chronic renal failure (CRF).
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Antioxidantes/farmacología , Ácido Hipocloroso/química , Riñón/efectos de los fármacos , Riñón/patología , Mitocondrias/efectos de los fármacos , Oligopéptidos/farmacología , Albúmina Sérica/farmacología , Animales , Biomarcadores/metabolismo , Citoprotección/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Fibrosis , Riñón/metabolismo , Riñón/fisiología , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Albúmina Sérica/química , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVE: Whether statins can slow down the progression of chronic kidney disease (CKD) remains controversial. We performed a meta-analysis to evaluate the effects of statin therapy on disease progression in adult patients with CKD who did not require dialysis therapy. METHODS: We searched the electronic databases for relevant randomized controlled trials (RCTs) published by February 2015. Random-effects meta-analysis of RCTs was used to pool the renal outcomes of the patients. RESULTS: Twenty-eight studies (30 RCTs) involving a total of 45 688 participants were included in the analysis. Compared with the control groups, statins produced no effects in preventing end-stage renal disease (ESRD) [relative risks (RR) 0.98, 95% confidence intervals (CI): 0.91-1.05] and in reducing the risk of doubling of the serum creatinine level (RR 1.43, 95% CI: 0.26-7.79). Statin therapy was associated with a lowered risk of estimated glomerular filtration rate (eGFR) reduction by 25% or more (RR 0.91, 95% CI: 0.83-0.99) and delayed the reduction of eGFR [standardized mean differences (SMD) 0.04, 95% CI: 0.02-0.07]. In subgroup analyses, the benefit of statins on changes in eGFR was statistically significant in patients with moderate CKD (SMD 0.09, 95% CI 0.04-0.13). Among different statins, atorvastatin was associated with a beneficial effect on kidney function (SMD 0.10, 95% CI 0.03-0.17). Patients who received high-intensity statin therapy showed significant changes in eGFR (SMD 0.12, 95% CI: 0.02-0.21). CONCLUSION: Statin therapies may not prevent ESRD or doubling of serum creatinine level, but can improve GFR or delay the reduction of GFR in CKD patients. The therapeutic effects are associated with the patients' baseline eGFR levels, statin types and therapy intensity.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Fallo Renal Crónico/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Adulto , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Hypochlorite-modified albumin (HOCl-alb) has been linked to endothelial dysfunction, which plays an important role in the development of hypertension, diabetes, and chronic kidney disease. However, whether HOCl-alb induces endothelial dysfunction via vascular inflammation and whether a signaling pathway is involved are unknown and have not been investigated. HOCl-alb was found to upregulate ICAM-1 expression in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent manner. HOCl-alb time-dependently phosphorylated ERK1/2 and p38(MAPK). HOCl-alb also activated NF-κB. ICAM-1 expression was dose-dependently inhibited by U0126 (a specific inhibitor of MEK1/2, a signal upstream from ERK1/2), SB203580 (a specific inhibitor of p38(MAPK)), and SN50 (a specific inhibitor of NF-κB). U0126 and SB203580 both counteracted the activation of NF-κB, whereas the phosphorylation of ERK1/2 and p38(MAPK) was not blocked by SN50. ERK1/2 phosphorylation was blocked by U0126 but not by SB203580, and p38(MAPK) activity was reduced by SB203580 but not by U0126. Apocynin, a specific NADPH oxidase (NOX) inhibitor, inhibited ICAM-1 expression and the activity of ERK1/2, p38(MAPK), and NF-κB. These results indicate that HOCl-alb-induced ICAM-1 expression is caused by the activation of a redox-sensitive intracellular signal cascade involving ERK1/2 and p38(MAPK), culminating in the activation of NF-κB and involving NOXs among the upstream signals.
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Acetofenonas/química , Albúminas/química , Ácido Hipocloroso/química , Molécula 1 de Adhesión Intercelular/metabolismo , Sistema de Señalización de MAP Quinasas , FN-kappa B/metabolismo , Células Endoteliales/citología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Microscopía Fluorescente , Estrés Oxidativo , Fosforilación , Transducción de Señal , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The layer-by-layer assembly (LBL) is a new method of thin film deposition often used for oppositely charged polyelectrolytes. LBL technique has been extensively used to make multilayer films of polyions with biomolecules such as proteins, enzymes and DNA. It can also be successfully applied to the preparation of thin films of nanoparticles. Ultrathin multilayer films containing a polyoxometalate (Eu(PW11)2)m and PEI were prepared using layer-by-layer assembly method in the present work. The stable multilayer films were assembled by alternate adsorption of negatively charged POM and positively charged polyelectrolytes from their aqueous dispersions. The growth of the multilayer films is regular. The proposed novel immobilized method exhibited good stability and the photoluminescent behavior of films at room temperature was investigated to show the Eu3+ characteristic emission pattern, which is important for practical application.