The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD.
diabetic kidney disease (dKd) is a severe form of microangiopathy among diabetic patients, of which podocyte injury is one of the more predominant features. There is increasing evidence to suggest that mitochondrial dysfunction is associated with podocyte injury, thus contributing to the progression of DKD. Initially identified as a p53 target protein, the endogenous antioxidant protein, sestrin-2 (sesn2), has recently attracted attention due to its potential function in various inflammatory diseases. However, the association between sesn2 and podocytes in dKd remains unclear. In the present study, to elucidate the role of sesn2 in podocyte mitochondrial dysfunction, the effects of sesn2 on the regulation of AMP-activated protein kinase (AMPK) were examined in vitro and in vivo. Abnormal mitochondria were found in rats with streptozotocin-induced diabetes, and hyperglycemia downregulated the expression of sesn2. The upregulation of sesn2 increased the level of AMPK phosphorylation, and thus ameliorated mitochondrial dysfunction under high glucose conditions (HG). On the whole, these results suggest that sesn2 is associated with mitochondrial dysfunction in podocytes under HG conditions. In addition, the decreased expression of sesn2 may be a therapeutic target for dKd.
We concluded that multiple school and home environmental factors were related to respiratory and allergic symptoms. High asthma burden and smoking are important public health problems in Romania. Future studies including larger sample size and exposure measurements are needed to confirm our findings.
Few studies have evaluated the short-term association between hospital admissions and individual exposure to ambient particulate matter (PM2.5). Particularly, no studies focused on hospital admissions for chronic obstructive pulmonary disease (COPD) at the individual level. We assessed the short-term effects of PM2.5 on hospitalization admissions for COPD in Guangzhou, China, during 2014–2015, based on satellite-derived estimates of ambient PM2.5 concentrations at a 1-km resolution near the residential address as individual-level exposure for each patient. Around 40,002 patients with COPD admitted to 110 hospitals were included in this study. A time-stratified case-crossover design with conditional logistic regression models was applied to assess the effects of PM2.5 based on a 1-km grid data of aerosol optical depth provided by the National Aeronautics and Space Administration on hospital admissions for COPD. Further, we performed stratified analyses by individual demographic characteristics and season of hospital admission. Around 10 μg/m3 increase in individual-level PM2.5 was associated with an increase of 1.6% (95% confidence interval [CI]: 0.6%, 2.7%) in hospitalization for COPD at a lag of 0–5 days. The impact of PM2.5 on hospitalization for COPD was greater significantly in males and patients admitted in summer. Our study strengthened the evidence for the adverse effect of PM2.5 based on satellite-based individual-level exposure data.
Extensive evidence suggests that ambient air pollution contributes to a higher risk of hospital admissions for cerebrovascular diseases; however, its association with admissions for sequelae of stroke remains unclear. A time‐stratified case‐crossover study was conducted among 31,810 older adults who were admitted to hospital for sequelae of stroke in Guangzhou, China during 2016–2019. For each subject, daily residential exposure to fine particulate matter (PM2.5), inhalable particulate matter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3) was extracted from a validated grid data set. Conditional logistic regression models were used for exposure‐response analyses. In single‐pollutant models, each interquartile range (IQR) increase of lag 04‐day exposure to CO (IQR: 0.25 mg/m3) and lag 3‐day exposure to O3 (69.6 μg/m3) was significantly associated with a 4.53% (95% confidence interval: 1.67%, 7.47%) and 5.63% (1.92%, 9.48%) increase in odds of hospital admissions for sequelae of stroke, respectively. These associations did not significantly vary across age or sex. With further adjustment for each of the other pollutants in 2‐pollutant models, the association for CO did not change significantly, while the association for O3 disappeared. We estimated that 7.72% of the hospital admissions were attributable to CO exposures. No significant or consistent association was observed for exposure to PM2.5, PM10, SO2, or NO2. In conclusion, short‐term exposure to ambient CO, even at levels below the WHO air quality guideline, was significantly associated with an increased odds of hospital admissions for sequelae of stroke, which may lead to considerable excess hospital admissions.
Chronic obstructive pulmonary disease (COPD) is a major cause of chronic diseases causing considerable social and economic burden globally. Despite substantial evidence on temperature-COPD association, few studies have investigated the acute effect of temperature variability (TV), a potential trigger of exacerbation of COPD disease, and it remains unknown what fraction of the disease burden of COPD is attributable to TV. Patients and Methods: Based on 71,070 COPD hospitalizations during 2013-2015 in Guangzhou, China, we conducted a time-series analysis using quasi-Poisson regression to assess the association between TV and hospital admission for COPD after adjusting for daily mean temperature. Short-term TV was captured by the standard deviation of hourly or daily temperatures across various exposure days. We also provided the fraction (total number) of COPD attributable to TV. Stratified analyses by admission route, sex, age, occupation, marital status and season were performed to identify vulnerable subpopulations. Results: We found a linear relationship between TV and COPD hospitalization, with a 1° C increase in hourly TV and daily TV associated with 4.3% (95%CI: 2.2-6.4) and 4.0% (2.3-5.8) increases in COPD, respectively. The greater relative risks of TV identified males, people aged 0-64 years, blue collar, and divorced/widowed people as vulnerable population. There were 12.0% (8500 cases) of COPD hospitalization attributable to hourly TV during the study period. Daily TV produced similar estimates of relative effects (relative risk) but grater estimates of absolute effects (attributable fraction) than hourly TV. Conclusion: We concluded that TV was an independent risk factor of COPD morbidity, especially among the susceptible subgroups. These findings would be helpful to guide the development of targeted public intervention.
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