Tubular epithelial loss has been shown to be responsible for the formation of atubular glomeruli leading to nephron decomposition and interstitial fibrosis in obstructive uropathy. Cells undergoing apoptosis and autophagic cell death play an important role in this process, yet the mechanisms are not fully understood. In this study, we aimed to investigate whether autophagy cooperating with apoptosis is associated with mitochondrial damage and whether oxidative stress plays an important role in the loss of tubular epithelium following unilateral ureteral obstruction. In this model, we demonstrated that there is coexistence of autophagy and apoptosis with tubular atrophy in obstructed proximal tubules. After unilateral ureteral obstruction (UUO), autophagy in proximal tubular cells was enhanced steadily up to 7 days in the obstructed kidney and declined thereafter, while apoptosis was induced in a time-dependent manner from 3 to 14 days. Mitochondrial structure and number also changed during UUO. Lipid peroxidation products, NOX4, and NADPH oxidase activity were also increased in the obstructed renal cortex, and peaked at 7 days. In vitro, we showed that H2O2 induced mitochondrial injury leading to autophagy and apoptosis through the Beclin 1 pathway and interference with Bcl-2 expression. Thus, our data demonstrate that oxidative stress leading to mitochondrial damage and driven autophagy-dependent cell death and apoptosis are important mechanisms of tubular decomposition in obstructive nephropathy.
Abstract. Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that regulates cell growth, differentiation, apoptosis and autophagy in various cell types. It has been shown that TGF-β1-driven autophagy represents a novel mechanism of tubular decomposition, leading to renal interstitial fibrosis. However, the exact mechanism by which TGF-β1 regulates autophagy is still poorly understood. In the present study, we investigated the effects of exogenous TGF-β1 on cultured human renal proximal tubular epithelial cells (HRPTEpiCs). Presence of TGF-β1 in the medium induced accumulation of autophagosomes in a time-and dose-dependent manner as seen by monitoring the marker LC3 by confocal fluorescence microscopy and immunoblotting. In addition, TGF-β1 induced upregulation of autophagy-related genes, Atg5, Atg7 and Beclin1. Importantly, increased generation of reactive oxygen species (ROS) and enhanced expression of NADPH oxidases were found to be associated with the TGF-β1-induced autophagy. Conversely, treatment with inhibitors of NADPH oxidase markedly reversed the autophagic effects of TGF-β1. Apoptotic effects were evaluated by the TUNEL assay, measuring mitochondrial membrane potential and monitoring expression of the pro-and anti-apoptotic genes, Bim and Bcl-2, respectively. Transcriptional silencing of the above three autophagy-related genes in HRPTEpiCs caused attenuation of TGF-β1-mediated apoptosis. Similarly, when autophagy was prevented at an early stage by application of 3-methyladenine, the pro-apoptotic effects of TGF-β1 were attenuated. These observations suggest that in HRPTEpiCs TGF-β1 promotes autophagy through the generation of ROS, which contributes to its proapoptotic effect. IntroductionAutophagy and apoptosis are two processes, through which injured/aged cells or organelles are eliminated (1,2). Autophagy, or the 'self-eating' function, is characterized by the presence of abundant double-membraned vacuoles called autophagosomes that sequester cytoplasm and cytosolic organelles, such as mitochondria and endoplasmic reticulum. Subsequently, the autophagosome fuses to a lysosome and its contents and inner membrane are degraded and recycled (3). Autophagy is usually regarded as a protective mechanism for cell survival under various conditions including nutrient deprivation and hypoxia (4). However, increasing evidence suggests that in response to excessive stress autophagy may be detrimental and can lead to cell death (5). Excessive autophagic activity may lead to cellular dysfunctions and induce death by destroying a large proportion of the cytosol and organelles, especially the mitochondria and the endoplasmic reticulum (ER) (6,7). The contribution of autophagy to cell death depends on the threshold of the stimuli. It either constitutes a stress adaptation aimed at suppressing apoptosis or conversely provides an alternative pathway to cell death (2,8).Tubular injury is the major contributor to reduction of renal function. Nephron loss can initiate from the tubular decomposition, follo...
The purpose of the study was to reveal the therapeutic effect of quercetin (QUE) nanoparticle complex on diabetic nephropathy (DN) by regulating the expression of intercellular adhesion molecular-1 (ICAM-1) on endothelium as compared to free QUE. QUE 10 mg/kg as a single abdominal subcutaneous injection daily for 8 weeks continuously in diabetic rats and 10 mg/kg QUE nanoparticle complex as a single abdominal subcutaneous injection every 5 days, continuously administered for 8 weeks to diabetic rats. Blood and left kidneys were collected; pathological change of kidney, renal function, oxidative stress level, blood glucose level, serum lipid, urine protein, and albumin/creatinine ratio were measured; and neutrophil adhesion, ICAM-1 expression, and CD11b + cells infiltration were observed. Both QUE and QUE nanoparticle complex preconditioning ameliorated the pathological damage of kidney and improved renal function, alleviated renal oxidative stress injury, restricted inflammatory cells infiltration, and downregulated the ICAM-1 expression as compared to DN group, while QUE nanoparticle complex significantly alleviated this effect.
Abstract. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), plays an important role in angiotension II (Ang II)-induced hypertensive renal injury associated with pro-inflammatory responses, tubular functional damage and cellular apotosis. In this study, we report on the role of LOX-1 in Ang II-induced oxidative functional damage and underlying signaling in human renal proximal tubular epithelial cells (HRPTEpiCs). The exposure to Ang II enhanced the expression of the NADPH oxidases (the p22phox, p47phox and Nox4 subunits), LOX-1 and the adhesion molecule, ICAM-1. It also promoted monocytic U937 cell adherences to HRPTEpiCs, increased reactive oxygen species formation and stimulated apotosis, which was concomitant with an increase in the activation of p38 and p44/42 mitogen-activated protein kinases (MAPK). Furthermore, the Ang II treatment disturbed the balance of the Bcl-2 family proteins, destabilized mitochondrial membrane potential, and subsequently triggered the release of cytochrome c into the cytosol, causing the activation of caspase-3. The NADPH oxidase inhibitors and LOX-1 small interfering RNA markedly ameliorated these detrimental effects by reducing LOX-1 expression and MAPK activation. The p38 and p44/42MAPK inhibitors also inhibited the Ang II-induced functional damage without affecting LOX-1 expression in the HRPTEpiCs. These observations suggest that LOX-1 mediates Ang II-induced renal tubular epithelial dysfunction. In addition, MAPK pathway activation occurs downstream of the Ang II/reactive oxygen species/ LOX-1 cascade.
IntroductionInsulin has shown antioxidation and cytoprotective effects to decrease heart ischemia/reperfusion injury (HI/RI) in diabetes mellitus (DM), but the role of insulin/poly(ethylene glycol)-carboxymethyl chitosan (PEG-CMCS) on HI/RI in DM is not known. This research explored whether insulin/PEG-CMCS revealed a protective effect on HI/RI in DM through ornithine decarboxylase (ODC)/polyamine systems.Materials and methodsDiabetes was induced via streptozotocin (STZ) in Sprague Dawley (SD) rats, which suffered from HI via blocking the left circumflex artery for 45 minutes, followed by 2 hours of reperfusion. α-Difluoromethylornithine-ethylglyoxal bis (guanylhydrazone) (DFMO-EGBG) and insulin/PEG-CMCS were administered to diabetic rats to explore their roles on severity of HI/RI.ResultsInsulin could be fleetly and efficiently loaded via the nanocarrier PEG-CMCS at pH =6, showing efficient loading and stable release. In addition, insulin/PEG-CMCS showed significant hypoglycemic activity in diabetic rats. On the other hand, ischemia/reperfusion obviously augmented the contents of creatine kinase (CK), lactic dehydrogenase (LDH), putrescine (Pu), myocardial infarct size, and NF-κB and spermidine/spermine N′-acetyltransferase (SSAT) expressions and decreased the levels of spermine (Sp), polyamine pools (PAs), heart rate (HR), coronary blood flow (CF), left ventricular developed pressure (LVDP), and ODC expression, compared with Sham. Administration of insulin and insulin/PEG-CMCS both reduced the contents of CK, LDH, Pu, myocardial infarct size, and NF-κB and SSAT expressions and increased the levels of Sp, PAs, HR, CF, LVDP, and ODC expression, while insulin/PEG-CMCS significantly indicated the protective results, and DFMO-EGBG showed the opposite effects.ConclusionThe research showed that insulin/PEG-CMCS could play a protective effect on HR/RI in diabetic rats via its antioxidative, antiapoptotic, and anti-inflammatory roles and modulating ODC/polyamine systems.
YSJZG improved the renal function in rats with CRF and inhibited the progression of tubulointerstitial fibrosis by dose-dependently alleviating mitochondrial injury, restoring the expression of Tfam and PCG-1α, and inhibiting renal tubular epithelial cell apoptosis through inhibiting activation of reactive oxygen species-MAPK signaling.
This study aimed to investigate the effect of Quanzhenyiqitang on alveolar macrophages (AMs) in a rat model of chronic obstructive pulmonary disease (COPD). In addition, the induction of apoptosis and regulation of histone deacetylase 2 (HDAC2) was studied to elucidate the underlying mechanisms of Quanzhenyiqitang treatment of COPD. Quanzhenyiqitang-treated serum was applied to AMs obtained from rats with COPD. A blank (control) group, an untreated serum group and an aminophylline group were also observed to evaluate the differences in AM apoptosis status, as well as the expression levels of caspase-9, caspase-8 and HDAC2. Compared with the control group, Quanzhenyiqitang-treated serum resulted in higher levels of caspase-9 and caspase-8 expression, increased apoptosis of AMs and increased expression of HDAC2 by AMs. In conclusion, Quanzhenyiqitang is capable of inducing apoptosis of AMs, which are the primary inflammatory cells in COPD, and modulating the expression of the important inflammatory factor HDAC2, producing an overall anti-inflammatory effect.
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