Acute kidney injury (AKI) increases the risk of chronic kidney disease (CKD), but the mechanisms of CKD development after AKI remain unclear. Recent studies have elucidated that autophagy protects ...against AKI, but the role of autophagy during the AKI-to-CKD transition is controversial. Beclin1 is a key molecule for autophagy as well as endocytosis and phagocytosis. Shi et al. demonstrate that Beclin1 activates autophagy and is a promising therapeutic target for AKI-to-CKD transition.
Autophagy, an evolutionarily conserved cytoplasmic degradation system, has been implicated as a convergent mechanism in various longevity pathways. Autophagic activity decreases with age in several ...organisms, but the underlying mechanism is unclear. Here, we show that the expression of Rubicon, a negative regulator of autophagy, increases in aged worm, fly and mouse tissues at transcript and/or protein levels, suggesting that an age-dependent increase in Rubicon impairs autophagy over time, and thereby curtails animal healthspan. Consistent with this idea, knockdown of Rubicon extends worm and fly lifespan and ameliorates several age-associated phenotypes. Tissue-specific experiments reveal that Rubicon knockdown in neurons has the greatest effect on lifespan. Rubicon knockout mice exhibits reductions in interstitial fibrosis in kidney and reduced α-synuclein accumulation in the brain. Rubicon is suppressed in several long-lived worms and calorie restricted mice. Taken together, our results suggest that suppression of autophagic activity by Rubicon is one of signatures of aging.
Excessive fat intake contributes to the progression of metabolic diseases
cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the role of lysosomal dysfunction and ...impaired autophagic flux in the pathogenesis of lipotoxicity in the kidney. In mice, a high-fat diet (HFD) resulted in an accumulation of phospholipids in enlarged lysosomes within kidney proximal tubular cells (PTCs). In isolated PTCs treated with palmitic acid, autophagic degradation activity progressively stagnated in association with impaired lysosomal acidification and excessive lipid accumulation. Pulse-chase experiments revealed that the accumulated lipids originated from cellular membranes. In mice with induced PTC-specific ablation of autophagy, PTCs of HFD-mice exhibited greater accumulation of ubiquitin-positive protein aggregates normally removed by autophagy than did PTCs of mice fed a normal diet. Furthermore, HFD-mice had no capacity to augment autophagic activity upon another pathologic stress. Autophagy ablation also exaggerated HFD-induced mitochondrial dysfunction and inflammasome activation. Moreover, renal ischemia-reperfusion induced greater injury in HFD-mice than in mice fed a normal diet, and ablation of autophagy further exacerbated this effect. Finally, we detected similarly enhanced phospholipid accumulation in enlarged lysosomes and impaired autophagic flux in the kidneys of obese patients compared with nonobese patients. These findings provide key insights regarding the pathophysiology of lipotoxicity in the kidney and clues to a novel treatment for obesity-related kidney diseases.
Fabrication and characterization of methylammonium lead iodide perovskite solar cells incorporated with methylammonium bromide (MABr), formamidinium bromide (FABr), and decaphenylcyclopentasilane ...(DPPS) were performed. Additive effect of MABr or FABr into the perovskite layers inserted with DPPS as hole-transporting layer was investigated. Addition of 5% MABr or FABr into the perovskite layer improved the short-circuit current density, shunt resistance, and open-circuit voltages, which depended on the uniform morphologies while suppressing defects and pinholes in the perovskite layer. The stabilities of the photovoltaic performance depended on the degree of incorporation of MABr or FABr with the DPPS layer, which suppressed decomposition in the perovskite layer.
High throughput synthesis of atomic layer graphene membrane by chemical vapor deposition (CVD) is one of key technologies to establish industrial applications. Here we report the details of the ...initial stage of graphene growth on copper substrate by radio frequency (RF) plasma-assisted CVD under low pressure and compare the nucleation rate and the growth rate with conventional thermal CVD. Two-dimensional growth rate of graphene by plasma-assisted CVD is 100 and 1000 times larger than that of thermal CVD at 950 °C and at 750 °C, respectively. It is found that graphene growth is governed by the diffusion of active carbon species on the copper surface with a very low activation energy of 0.4 eV at low-temperature(≦ 850 °C) and low pressure. The high growth rate of plasma-assisted CVD of graphene is discussed.
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•Decaphenylcyclopentasilane-inserted perovskite solar cells were characterized.•Conversion efficiencies of DPPS-inserted cells were improved by annealing at 220 °C.•Surface coverage ...of the perovskite layer was improved by the DPPS insertion.•The DPPS layer suppressed the PbI2 formation and improved the device stability.•After 4 weeks, the 190 °C-heated device provided the highest conversion efficiency.
Perovskite solar cells, in which decaphenylcyclopentasilane (DPPS) layers were formed on the surface of the CH3NH3PbI3 perovskite layer, were fabricated and characterized. The photovoltaic properties were improved by controlling the annealing temperature of the perovskite layer. For perovskite layers annealed at high temperatures of ~200 °C, the perovskite crystals were densely formed and the surface coverage of the perovskite layer was improved. The DPPS-laminated devices suppressed the formation of PbI2 crystals and the stability was improved by the DPPS layer.
Evidence of a protective role of autophagy in kidney diseases has sparked interest in autophagy as a potential therapeutic strategy. However, understanding how the autophagic process is altered in ...each disorder is critically important in working toward therapeutic applications.
Using cultured kidney proximal tubule epithelial cells (PTECs) and diabetic mouse models, we investigated how autophagic activity differs in type 1 versus type 2 diabetic nephropathy. We explored nutrient signals regulating starvation-induced autophagy in PTECs and used autophagy-monitoring mice and PTEC-specific autophagy-deficient knockout mice to examine differences in autophagy status and autophagy's role in PTECs in streptozotocin (STZ)-treated type 1 and
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type 2 diabetic nephropathy. We also examined the effects of rapamycin (an inhibitor of mammalian target of rapamycin mTOR) on vulnerability to ischemia-reperfusion injury.
Administering insulin or amino acids, but not glucose, suppressed autophagy by activating mTOR signaling. In
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mice, autophagy induction was suppressed even under starvation; in STZ-treated mice, autophagy was enhanced even under fed conditions but stagnated under starvation due to lysosomal stress. Using knockout mice with diabetes, we found that, in STZ-treated mice, activated autophagy counteracts mitochondrial damage and fibrosis in the kidneys, whereas in
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mice, autophagic suppression jeopardizes kidney even in the autophagy-competent state. Rapamycin-induced pharmacologic autophagy produced opposite effects on ischemia-reperfusion injury in STZ-treated and
mice.
Autophagic activity in PTECs is mainly regulated by insulin. Consequently, autophagic activity differs in types 1 and 2 diabetic nephropathy, which should be considered when developing strategies to treat diabetic nephropathy by modulating autophagy.
Advanced glycation end products (AGEs) are involved in the progression of diabetic nephropathy. AGEs filtered by glomeruli or delivered from the circulation are endocytosed and degraded in the ...lysosomes of kidney proximal tubular epithelial cells (PTECs). Autophagy is a highly conserved degradation system that regulates intracellular homeostasis by engulfing cytoplasmic components. We have recently demonstrated that autophagic degradation of damaged lysosomes is indispensable for cellular homeostasis in some settings. In this study, we tested the hypothesis that autophagy could contribute to the degradation of AGEs in the diabetic kidney by modulating lysosomal biogenesis. Both a high-glucose and exogenous AGE overload gradually blunted autophagic flux in the cultured PTECs. AGE overload upregulated lysosomal biogenesis and function in vitro, which was inhibited in autophagy-deficient PTECs because of the impaired nuclear translocation of transcription factor EB. Consistently, streptozotocin-treated, PTEC-specific, autophagy-deficient mice failed to upregulate lysosomal biogenesis and exhibited the accumulation of AGEs in the glomeruli and renal vasculature as well as in the PTECs, along with worsened inflammation and fibrosis. These results indicate that autophagy contributes to the degradation of AGEs by the upregulation of lysosomal biogenesis and function in diabetic nephropathy. Strategies aimed at promoting lysosomal function hold promise for treating diabetic nephropathy.
No literature review exists on Mycoplasma pneumoniae-associated mild encephalitis/encepharopathy with a reversible splenial lesion (MERS).
M.pneumoniae-associated MERS cases were searched till August ...2016 using PubMed/Google for English/other-language publications and Ichushi ( http://www.jamas.or.jp/ ) for Japanese-language publications. Inclusion criteria were children fulfilling definition for encephalitis, M.pneumoniae infection, and neuroimaging showing hyperintensity in the splenium of the corpus callosum (SCC) alone (type I) or SCC/other brain areas (type II).
We described two children with type I and II M.pneumoniae-associated MERS. Thirteen cases found by the search and our 2 cases were reviewed. Mean age, male/female ratio, duration of prodromal illness was 8.3 years, 1.5 and 3.5 days. The most common neurological symptom was drowsiness, followed by abnormal speech/behavior, ataxia, seizure, delirium, confusion, tremor, hallucination, irritability, muscle weakness, and facial nerve paralysis. Fever was the most common non-neurological symptom, followed by cough, headache, gastrointestinal symptoms, headache, lethargy and dizziness. Seizure and respiratory symptoms were less common. All were diagnosed for M.pneumoniae by serology. Cerebrospinal fluid (CSF) M.pneumoniae was undetectable by PCR in the 3 patients. Three patients were clarithromycin-resistant. Leukocytosis, positive C-reactive protein, hyponatremia, CSF pleocytosis and slow wave on electroencephalography frequently occurred. All except 2 were type I MERS. Neuroimaging abnormalities disappeared within 18 days in the majority of patients. All type I patients completely recovered within 19 days. Two type II patients developed neurological sequelae, which recovered 2 and 6 months after onset.
Prognosis of M.pneumoniae-associated MERS is excellent. Type II MERS may increase a risk of neurological sequelae.
Autophagy plays an essential role in cellular homeostasis through the quality control of proteins and organelles. Although a time-dependent decline in autophagic activity is believed to be involved ...in the aging process, the issue remains controversial. We previously demonstrated that autophagy maintains proximal tubular cell homeostasis and protects against kidney injury. Here, we extend that study and examine how autophagy is involved in kidney aging. Unexpectedly, the basal autophagic activity was higher in the aged kidney than that in young kidney; short-term cessation of autophagy in tamoxifen-inducible proximal tubule-specific autophagy-deficient mice increased the accumulation of SQSTM1/p62- and ubiquitin-positive aggregates in the aged kidney. By contrast, autophagic flux in response to metabolic stress was blunted with aging, as demonstrated by the observation that transgenic mice expressing a green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3B fusion construct, showed a drastic increase of GFP-positive puncta in response to starvation in young mice compared to a slight increase observed in aged mice. Finally, proximal tubule-specific autophagy-deficient mice at 24 mo of age exhibited a significant deterioration in kidney function and fibrosis concomitant with mitochondrial dysfunction as well as mitochondrial DNA abnormalities and nuclear DNA damage, all of which are hallmark characteristics of cellular senescence. These results suggest that age-dependent high basal autophagy plays a crucial role in counteracting kidney aging through mitochondrial quality control. Furthermore, a reduced capacity for upregulation of autophagic flux in response to metabolic stress may be associated with age-related kidney diseases.
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