BRG1 accelerates mesothelial cell senescence and peritoneal fibrosis by inhibiting mitophagy through repression of OXR1.

Peritoneal mesothelial cell senescence promotes the development of peritoneal dialysis (PD)-related peritoneal fibrosis. We previously revealed that Brahma-related gene 1 (BRG1) is increased in peritoneal fibrosis yet its role in modulating peritoneal mesothelial cell senescence is still unknown. This study evaluated the mechanism of BRG1 in peritoneal mesothelial cell senescence and peritoneal fibrosis using BRG1 knockdown mice, primary peritoneal mesothelial cells and human peritoneal samples from PD patients. The augmentation of BRG1 expression accelerated peritoneal mesothelial cell senescence, which attributed to mitochondrial dysfunction and mitophagy inhibition. Mitophagy activator salidroside rescued fibrotic responses and cellular senescence induced by BRG1. Mechanistically, BRG1 was recruited to oxidation resistance 1 (OXR1) promoter, where it suppressed transcription of OXR1 through interacting with forkhead box protein p2. Inhibition of OXR1 abrogated the improvement of BRG1 deficiency in mitophagy, fibrotic responses and cellular senescence. In a mouse PD model, BRG1 knockdown restored mitophagy, alleviated senescence and ameliorated peritoneal fibrosis. More importantly, the elevation level of BRG1 in human PD was associated with PD duration and D/P creatinine values. In conclusion, BRG1 accelerates mesothelial cell senescence and peritoneal fibrosis by inhibiting mitophagy through repression of OXR1. This indicates that modulating BRG1-OXR1-mitophagy signaling may represent an effective treatment for PD-related peritoneal fibrosis.

Metadherin orchestrates PKA and PKM2 to activate ß-catenin signaling in podocytes during proteinuric chronic kidney disease.

Podocyte damage is the major cause of glomerular injury and proteinuria in multiple chronic kidney diseases. Metadherin (MTDH) is involved in podocyte apoptosis and promotes renal tubular injury in mouse models of diabetic nephropathy and renal fibrosis; however, its role in podocyte injury and proteinuria needs further exploration. Here, we show that MTDH was induced in the glomerular podocytes of patients with proteinuric chronic kidney disease and correlated with proteinuria. Podocyte-specific knockout of MTDH in mice reversed proteinuria, attenuated podocyte injury, and prevented glomerulosclerosis after advanced oxidation protein products challenge or adriamycin injury. Furthermore, specific knockout of MTDH in podocytes repressed ß-catenin phosphorylation at the Ser675 site and inhibited its downstream target gene transcription. Mechanistically, on the one hand, MTDH increased cAMP and then activated protein kinase A (PKA) to induce ß-catenin phosphorylation at the Ser675 site, facilitating the nuclear translocation of MTDH and ß-catenin; on the other hand, MTDH induced the deaggregation of pyruvate kinase M2 (PKM2) tetramers and promoted PKM2 monomers to enter the nucleus. This cascade of events leads to the formation of the MTDH/PKM2/ß-catenin/CBP/TCF4 transcription complex, thus triggering TCF4-dependent gene transcription. Inhibition of PKA activity by H-89 or blockade of PKM2 deaggregation by TEPP-46 abolished this cascade of events and disrupted transcription complex formation. These results suggest that MTDH induces podocyte injury and proteinuria by assembling the ß-catenin-mediated transcription complex by regulating PKA and PKM2 function.

The relationship between decline rate of residual renal function in the first year and mortality in peritoneal dialysis patients.

INTRODUCTION: To assess the relationship between the rate of residual renal function (RRF) decline in the first year and all-cause and cardiovascular mortality in peritoneal dialysis (PD) patients. METHODS: Incident PD patients were divided into two groups by the corresponding RRF decline value, when hazard ratio (HR) = 1 was found by the restricted cubic spline. The associations of rate of decline of RRF in the first year with mortality were evaluated. RESULTS: Of 497 PD patients, 122 patients died. After adjusting for confounding factors, patients in fast-decline group had a significant increase risk of all-cause and cardiovascular mortality (HR: 1.97 and 2.09, respectively). Each 0.1-mL/min/1.73 m2 /month decrease in RRF in the first year of PD was associated with a 19% and 20% higher risk of all-cause and cardiovascular mortality, respectively. CONCLUSIONS: Faster decline of RRF in the first year was independently associated with all-cause and cardiovascular mortality in PD patients.

Renal Fibrosis Is Alleviated through Targeted Inhibition of IL-11-Induced Renal Tubular Epithelial-to-Mesenchymal Transition.

Renal fibrosis is a pathologic process that leads to irreversible renal failure without effective treatment. Epithelial-to-mesenchymal transition (EMT) plays a key role in this process. The current study found that aberrant expression of IL-11 is critically involved in tubular EMT. IL-11 and its receptor subunit alpha-1 (IL-11Rα1) were significantly induced in renal tubular epithelial cells (RTECs) in unilateral ureteral obstruction (UUO) kidneys, co-localized with transforming growth factor-ß1. IL-11 knockdown ameliorated UUO-induced renal fibrosis in vivo and transforming growth factor-ß1-induced EMT in vitro. IL-11 intervention directly induced the transdifferentiation of RTECs to the mesenchymal phenotype and increased the synthesis of profibrotic mediators. The EMT response induced by IL-11 was dependent on the sequential activation of STAT3 and extracellular signal-regulated kinase 1/2 signaling pathways and the up-regulation of metadherin in RTECs. Micheliolide (MCL) competitively inhibited the binding of IL-11 with IL-11Rα1, suppressing the activation of STAT3 and extracellular signal-regulated kinase 1/2-metadherin pathways, ultimately inhibiting renal tubular EMT and interstitial fibrosis induced by IL-11. In addition, treatment with dimethylaminomicheliolide, a pro-drug of MCL for in vivo use, significantly ameliorated renal fibrosis exacerbated by IL-11 in the UUO model. These findings suggest that IL-11 is a promising target in renal fibrosis and that MCL/dimethylaminomicheliolide exerts its antifibrotic effect by suppressing IL-11/IL-11Rα1 interaction and blocking its downstream effects.

Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis.

BACKGROUND: Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown. METHODS: The effects of MCL on BRG1-induced fibrotic responses and TGF-ß1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed. RESULTS: BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-ß1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-ß1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-ß1-induced fibrotic responses and blocked TGF-ß1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-ß1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-ß1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-ß1-Smad2/3 signaling pathway. CONCLUSION: Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis.

N-methylpiperazine-diepoxyovatodiolide ameliorates peritoneal fibrosis via suppressing TGF-ß/Smad and JAK/STAT signaling pathway.

Peritoneal fibrosis (PF) is the main cause of peritoneal ultrafiltration failure in patients undergoing long-term peritoneal dialysis (PD). Epithelial-mesenchymal transition (EMT) is the key pathogenesis of PF. However, currently, no specific treatments are available to suppress PF. N-methylpiperazine-diepoxyovatodiolide (NMPDOva) is a newly synthesized compound that involves a chemical modification of ovatodiolide. In this study, we aimed to explore the antifibrotic effects of NMPDOva in PD-related PF and underlying mechanisms. A mouse model of PD-related PF was established via daily intraperitoneal injection of 4.25% glucose PD fluid. In vitro studies were performed using the transforming growth factor-beta1 (TGF-ß1)-stimulated HMrSV5 cell line. Pathological changes were observed, and fibrotic markers were significantly elevated in the peritoneal membrane in mice model of PD-related PF. However, NMPDOva treatment significantly alleviated PD-related PF by decreasing the extracellular matrix accumulation. NMPDOva treatment decreased the expression of fibronectin, collagen Ⅰ, and alpha-smooth muscle actin (α-SMA) in mice with PD-related PF. Moreover, NMPDOva could alleviate TGF-ß1-induced EMT in HMrSV5 cells, inhibited phosphorylation and nuclear translocation of Smad2/3, and increased the expression of Smad7. Meanwhile, NMPDOva inhibited phosphorylation of JAK2 and STAT3. Collectively, these results indicated that NMPDOva prevents PD-related PF by inhibiting the TGF-ß1/Smad and JAK/STAT signaling pathway. Therefore, because of these antifibrotic effects, NMPDOva may be a promising therapeutic agent for PD-related PF.

Synergistic mechanism and degradation kinetics for atrazine elimination by integrated N-ZnO/g-C3N4/solar light/oxidant.

In this study, an N-ZnO/g-C3N4 (g-N-Z) Z-scheme photocatalyst was constructed using hydrothermal and high-temperature calcination. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and other tests were employed to characterise the catalytic material. The results showed that after N-ZnO modification, the separation efficiency of the photoinduced charge pairs and the utilisation of sunlight in the composites were improved. The kinetics experiments indicated that the degradation of atrazine (ATZ) in the g-N-Z/PDS/solar system was significantly better than that in the PDS/solar system. Under the action of the g-N-Z/PDS/solar system, the degradation rate of ATZ reached 83.88%, whereas in the PDS/solar system, it was only 31.76%. In addition, it was found that increasing the PDS concentration, g-N-Z dosage, and solution acidity effectively accelerated the removal of ATZ. The presence of HCO3-/CO32-, Cl-, and natural organic matter (NOM) inhibited the oxidation efficiency of the g-N-Z/PDS/solar system. Moreover, the presence of multiple reactive oxygen species (ROS) was confirmed using radical scavenging experiments to determine the contribution of each active component. Twelve oxidation intermediates of ATZ were obtained via liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the mechanism of enhanced ATZ degradation in the g-N-Z/PDS/solar system was proposed. Actual water and cyclic photocatalytic experiments further suggest that g-N-Z has good application value in water treatment.

CuO@carbon nanofiber as an efficient peroxymonosulfate catalyst for mitigation of organic matter fouling in the ultrafiltration process.

Persulfate oxidation has been increasingly integrated with membrane separation for water purification, whereas the oxidizing ability of persulfate is relatively limited, and appropriate activation methods are urgently required. In this work, a novel catalyst of carbon nanofiber (CNF) supported CuO (CuO@CNF) was synthesized for peroxymonosulfate (PMS) activation. The micro-morphology showed that CuO nanoparticles were well dispersed on the CNF support, which solved the agglomeration problem of nanoparticles and improved the catalytic ability. Furtherly, PMS oxidation activated by CuO@CNF was proposed as a pre-processing means for improving ultrafiltration (UF) water purification efficiency and mitigating membrane fouling. The prepared CuO@CNF was more efficient than individual CNF and CuO in activating PMS for the reduction of various typical natural organic matter, improving permeation flux, and mitigating membrane fouling. The fouling control efficiencies were also verified by characterizing the membrane surface functional groups. The CuO@CNF catalyst could signally promote the oxidative capacity by generating a series of reactive oxygen species, thus enhancing the removal of organics with varying species and molecular weight ranges in surface water. With respect to the fouling condition, the specific permeation flux after filtration was improved from 0.25 to 0.61, with the removal rate of reversible fouling resistance reached 89.6%. The fouling mechanism was apparently altered, with both standard and complete blocking dominated throughout the filtration process. The findings are beneficial for the development of new strategies to improve membrane-based water purification efficiency.

Degradation of iopamidol by UV365/NaClO: Roles of reactive species, degradation mechanism, and toxicology.

The degradation of iopamidol (IPM) was investigated using a UV365/NaClO system. The reactive species (HO·, ClO·, ozone, Cl·, and Cl2-·) in the system were identified, and the changing trends of the percentage contributions of these reactive species to IPM removal under various conditions were systematically evaluated. The results showed that ClO· and HO· played the most significant roles in the apparent pseudo-first-order rate constants of IPM degradation (kobs, min-1) in the control experiment, and their percentage contributions to kobs were 41.31% and 34.45%, respectively. In addition, Cl· and Cl2-· together contributed 22% to the kobs. Furthermore, the contribution of ozone to the IPM removal could be neglected. The concentrations of these species increased significantly when the concentration of NaClO was increased from 50 µM to 200 µM, while the percentage contribution of ClO· to kobs was greatly increased. The concentrations and percentage contributions of HO· and ClO· decreased significantly as the solution pH increased from 5 to 9, with Cl2-· playing a greater role in the degradation of IPM under alkaline conditions. While Cl- or HCO3-/CO32- significantly promoted the generation of Cl2-· or CO3-·, neither had an obvious effect on kobs, suggesting that Cl2-· and CO3-· should have a certain reactivity with IPM. Compared with that of Cl2-·, the percentage contribution of ClO· and Cl· to kobs was more likely to be inhibited by NOM. In addition, the organic and inorganic oxidation products of IPM were detected. The oxidation mechanisms of IPM degradation in the UV365/NaClO system, such as the H-extraction reaction, deiodination, substitution reaction, amide hydrolysis, and amine oxidation, were proposed according to the obtained 15 organic products. No effect on acute toxicity towards Vibrio fischeri and Photobacterium phosphoreum was detected during the oxidation of IPM by the UV365/NaClO system. Furthermore, the engineering feasibility of the oxidation system was demonstrated, by the effective degradation of IPM in actual water. However, HOI rapidly accumulated during the removal of IPM in the UV365/NaClO system, which poses certain environmental risks and will needs to be investigated.

Coordinated effects of energy transition on air pollution mitigation and CO2 emission control in China.

China has made progress in energy transition to improve air quality, but still confronts challenges including further ambient PM2.5 reduction, O3 pollution mitigation, and CO2 emission control. To explore the coordinated effects of energy transition on air quality and carbon emission in the near term in China, we designed 4 scenarios in 2025 based on different projections of energy transition progress with varying end-of-pipe control level, in each of which we calculated emissions of major air pollutants and CO2, and simulated ambient PM2.5 and O3 concentrations. Results show that energy transition has disparate effects on emission reduction of different air pollutants and sectors, which largely depends on their current end-of-pipe control levels. The different effects on emission reduction may result in opposite variation tendencies of ambient PM2.5 and O3 concentration in a future scenario with aggressive energy transition policies and end-of-pipe control level in 2018. With the end-of-pipe control level strengthened in 2025, PM2.5 and O3 concentration could both reduce on the national scale, but the reduction of ambient O3 lags behind PM2.5, indicating the difficulty of O3 pollution control. As to CO2, national emission would go up in 2025 either implementing current or aggressive energy transition policies due to growing needs of electricity and on-road transportation, but emissions in most provinces could decline to below the 2018 level with aggressive energy transition policies because of substitution of clean energy in industrial, residential and off-road transportation sectors. The study results suggest strictly implementing restrictive end-of-pipe control measures along with energy transition to simultaneously reduce ambient PM2.5 and O3 concentration, and accelerating substitution of renewable energy in power sectors where electricity generation grows rapidly to synergistically control air pollution and CO2 emissions. Furthermore, the projection of CO2 emissions could provide references for short-term emission control targets from the perspective of air quality improvement.

Effect of peroxydisulfate oxidation catalyzed with ordered mesoporous carbons on controlling ultrafiltration membrane fouling by algal organic matter.

As typical ordered mesoporous carbons (OMCs) materials, CMK-3 and CMK-8 were proposed for catalyzing peroxydisulfate (PDS), and the OMCs/PDS process was combined with membrane filtration to remove algal extracellular organic matter and mitigate membrane fouling. The CMK-3/PDS process achieved substantial reduction of dissolved organic carbon and UV254, followed by CMK-8/PDS. The degradation behavior of fluorescent organics demonstrated the superior performance of OMCs/PDS, while the decomposition of high molecular weight (MW) compounds and generation of lower MW organics were observed. Generally, CMK-3 possessed higher catalytic activity on PDS compared with CMK-8 and powdered activated carbon. The CMK-3/PDS process distinctly decreased the fouling resistances for polyether sulfone and polyvinylidene fluoride membranes, with the reversible resistance reduced by 59.5-83.2% and irreversible resistance declined by 71.7-73.0%. In the meanwhile, CMK-3/PDS prolonged the volumes to the transition period, and postponed the cake layer's generation. The characterization of the membrane morphologies and chemical compositions also showed effective alleviation of fouling. The generated SO4-, OH, O2- and 1O2 as major active oxidation species provided radical as well as non-radical reaction ways for pollutants removal. Overall, our study provides some new ideas for membrane-based combined water purification processes.

Synergistic process using calcium peroxide and ferrous iron for enhanced ultrafiltration of Microcystis aeruginosa-laden water.

Algal blooms and eutrophication in natural surface water not only pose a threat to human health, but also adversely affect the water purification process. Ultrafiltration (UF) has been proved to be effective for the retention of algal cells, but its further application is still restricted by the relatively limited removal of algal organics and membrane fouling. To enhance the UF performance, a synergistic process using calcium peroxide and ferrous sulfate (CaO2/FeSO4) was proposed for the treatment of Microcystis aeruginosa-laden water. The results suggested that the removal of algal cells and organics, fluorescent components were effectively increased with the synergism of CaO2 and FeSO4. The particle size distribution and morphology revealed that the size of algal pollutants apparently increased due to the formation of algal flocs. With CaO2/FeSO4 pretreatment, the terminal specific flux of polyethersulfone and polyvinylidene fluoride membranes were increased by 75.0% and 56.5%, individually. The fouling resistances were significantly reduced, and the fouling mechanism transition to cake filtration was delayed. The membrane interface properties including morphologies and functional groups were characterized, further verifying the effectiveness. The in-situ formed Fe3+ integrated with Ca(OH)2 showed excellent coagulation effect, thus promoting the agglomeration of algal foulants. Simultaneously, the generated hydroxyl radical could improve the oxidative degradation of algal organics. In conclusion, the CaO2/FeSO4 strategy has great advantages and application prospects in enhancing UF performance for Microcystis aeruginosa-laden water treatment.

Coupling sodium percarbonate (SPC) oxidation and coagulation for membrane fouling mitigation in algae-laden water treatment.

To alleviate algal fouling in membrane water treatment processes, conventional technologies such as coagulation with poly aluminum chloride (PACl) has been widely adopted by many drinking water treatment plants. However, coagulation alone exhibited relatively weak removal effect for algal pollutants, and the coagulant residues due to the excess dosage also raised concerns. Thus, a novel process of coupling sodium percarbonate (SPC) oxidation and PACl coagulation was proposed, integrated with membrane filtration for algae-laden water treatment. The dosages of PACl and SPC were optimized, and the SPC dosing strategies were systematically compared. The changes in the characteristics of algal pollutants were investigated, and the results revealed that the resistance of algal foulants to aggregation was decreased, and the particle size of algal foulants became larger. With the synergism of coagulation and oxidation, the degradation of fluorescent organics was strengthened, and macromolecular biopolymers were decomposed into low molecular weight organics. The fouling control efficiency was further explored, and the results indicated that both irreversible and reversible fouling were effectively controlled, among which PACl/SPC (simultaneous treatment) performed best with the irreversible fouling reduced by 90.5%, while the efficiency of SPC-PACl (SPC followed by PACl) was relatively lower (57.3%). The fouling mechanism was altered by slowing the formation of cake filtration, and the reduction of algal cells played a more important role for the fouling alleviation. The interface properties of contaminated membranes (i.e., functional groups, images, and micromorphology) were characterized, and the efficiency of the proposed strategy was further verified. The proposed strategy exhibits great application values for improving membrane performance during algae-laden water treatment.

A comparative study of EOF and NMF analysis on downward trend of AOD over China from 2011 to 2019.

In recent decades China has experienced high-level PM2.5 pollution and then visible air quality improvement. To understand the air quality change from the perspective of aerosol optical depth (AOD), we adopted two statistical methods of Empirical Orthogonal Functions (EOF) and Non-negative Matrix Factorization (NMF) to AOD retrieved by MODIS over China and surrounding areas. Results showed that EOF and NMF identified the important factors influencing AOD over China from different angles: natural dusts controlled the seasonal variation with contribution of 42.4%, and anthropogenic emissions have larger contribution to AOD magnitude. To better observe the interannual variation of different sources, we removed seasonal cycles from original data and conducted EOF analysis on AOD monthly anomalies. Results showed that aerosols from anthropogenic sources had the greatest contribution (27%) to AOD anomaly variation and took an obvious downward trend, and natural dust was the second largest contributor with contribution of 17%. In the areas surrounding China, the eastward aerosol transport due to prevailing westerlies in spring significantly influenced the AOD variation over West Pacific with the largest contribution of 21%, whereas the aerosol transport from BTH region in winter had relative greater impact on the AOD magnitude. After removing seasonal cycles, biomass burning in South Asia became the most important influencing factor on AOD anomalies with contribution of 10%, as its interannual variability was largely affected by El Niño. Aerosol transport from BTH was the second largest contributor with contribution of 8% and showed a decreasing trend. This study showed that the downward trend of AOD over China since 2011 was dominated by aerosols from anthropogenic sources, which in a way confirmed the effectiveness of air pollution control policies.

The role of PAC adsorption-catalytic oxidation in the ultrafiltration performance for treating natural water: Efficiency improvement, fouling mitigation and mechanisms.

Powdered activated carbon (PAC) has turned out to be an efficient adsorbent in drinking water treatment, whereas its application integrated with membrane filtration is still controversial because of the combined fouling effect between organic pollutants and PAC. To this end, an integrated process of combining PAC adsorption-catalytic oxidation and membrane filtration was proposed for natural surface water treatment. The synergistic effect of PAC and peroxymonosulfate (PMS) was confirmed through the generation of reactive oxidation species, and both radical oxidative pathways (•OH, SO4•- and O2•-) and nonradical (1O2 and PMS) pathways involved in the process. The removal efficiency of DOC and UV254 was significantly strengthened by PAC/PMS, with removal rates of 56.1% and 64.9%, respectively. The integration of PAC and PMS could significantly enhance the reduction of fluorescent organics, and pollutants with varying molecular weights. The fouling condition of membrane was dramatically alleviated, with the flux increased by 38.9%, and the reversible and irreversible resistances declined by 79.7% and 48.3%, respectively. The major fouling mechanism was significantly changed, and complete pore blocking always played a dominant role, rather than cake filtration. The effectiveness of PAC/PMS was further verified by the characterization of membrane surface morphologies and functional groups. Moreover, the attractive interactions between foulants and membrane were converted to repulsive interactions with the pretreatment of PAC/PMS. The proposed synergistic process was efficient and convenient, which could significantly improve the purification efficiency of conventional PAC-UF system in drinking water treatment.

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/ß-catenin/autophagy axis.

Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/ß-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-ß1 (TGF-ß1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated ß-galactosidase (SA-ß-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (siRNA)-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT-263 in vivo. Moreover, BRG1 activated the Wnt/ß-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/ß-catenin pathway (ICG-001) or rapamycin (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf A1)-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/ß-catenin pathway, which ultimately contributes to the development of renal fibrosis.

circRNA_010383 Acts as a Sponge for miR-135a, and Its Downregulated Expression Contributes to Renal Fibrosis in Diabetic Nephropathy.

Diabetic nephropathy (DN), a vascular complication of diabetes, is the leading cause of death in patients with diabetes. The contribution of aberrantly expressed circular RNAs (circRNAs) to DN in vivo is poorly understood. Integrated comparative circRNA microarray profiling was used to examine the expression of circRNAs in diabetic kidney of db/db mice. We found that circRNA_010383 expression was markedly downregulated in diabetic kidneys, mesangial cells, and tubular epithelial cells cultured in high-glucose conditions. circRNA_010383 colocalized with miRNA-135a (miR-135a) and inhibited miR-135a function by directly binding to miR-135a. In vitro, the knockdown of circRNA_010383 promoted the accumulation of extracellular matrix (ECM) proteins and downregulated the expression of transient receptor potential cation channel, subfamily C, member 1 (TRPC1), which is a target protein of miR-135a. Furthermore, circRNA_010383 overexpression effectively inhibited the high-glucose-induced accumulation of ECM and increased TRPC1 levels in vitro. More importantly, the kidney target of circRNA_010383 overexpression inhibited proteinuria and renal fibrosis in db/db mice. Mechanistically, we identified that a loss of circRNA_010383 promoted proteinuria and renal fibrosis in DN by acting as a sponge for miR-135a. This study reveals that circRNA_010383 may be a novel therapeutic target for DN in the future.

Klotho retards renal fibrosis through targeting mitochondrial dysfunction and cellular senescence in renal tubular cells.

Chronic kidney disease (CKD) has a high prevalence worldwide and is an intricate issue to whole medical society. Renal fibrosis is the common pathological feature for various kinds of CKD. As an anti-aging protein, Klotho is predominantly expressed in renal tubular epithelial cells. Reports show Klotho could retard age-related renal fibrosis. Mitochondrial dysfunction plays an important role in cellular senescence. However, the role of Klotho in mitochondrial dysfunction in CKD has not yet been determined. In this study, we treated unilateral ischemia-reperfusion (UIRI) mice and cultured human renal tubular epithelial cells (HKC-8) with Klotho. We assessed renal fibrosis, cellular senescence, and Wnt/ß-catenin signaling. We also focused on mitochondrial function assessment. In UIRI mice, ectopic expression of Klotho greatly retarded fibrotic lesions and the activation of Wnt/ß-catenin signaling. Interestingly, Klotho significantly preserved mitochondrial mass, inhibited mitochondrial reactive oxygen species (ROS) production and restored the expression of mitochondrial respiration chain complex subunits. Consequently, Klotho restrained cellular senescence. In HKC-8 cells, Klotho significantly inhibited Wnt1- and Wnt9a-induced mitochondrial injury, cellular senescence, and fibrotic lesions. These results suggest Klotho has a protective role in renal function through targeted protection on mitochondria. This further broads the understanding of the beneficial efficacies of Klotho in CKD.

circRNA_010383 Acts as a Sponge for miR-135a and its Downregulated Expression Contributes to Renal Fibrosis in Diabetic Nephropathy.

Diabetic nephropathy (DN), a vascular complication of diabetes mellitus, is the leading cause of death in diabetic patients. The contribution of aberrantly expressed circRNAs to diabetic nephropathy in vivo is poorly understood. Integrated comparative circRNA microarray profiling was used to examine the expression of circRNAs in diabetic kidney of db/db mice. We found that circRNA_010383 expression was markedly downregulated in diabetic kidneys, mesangial cells and tubular epithelial cells cultured in high-glucose conditions. circRNA_010383 colocalized with microRNA-135a (miR-135a) and inhibited miR-135a function by directly binding to miR-135a. In vitro, the knockdown of circRNA_010383 promoted the accumulation of extracellular matrix (ECM) proteins and downregulated the expression of transient receptor potential cation channel, subfamily C, member (TRPC1), which is a target protein of miR-135a. Furthermore, circRNA_010383 overexpression effectively inhibited the high-glucose-induced accumulation of ECM and increased TRPC1 levels in vitro More importantly, the kidney-target of circRNA_010383 overexpression inhibited proteinuria and renal fibrosis in db/db mice. Mechanistically, we identified that a loss of circRNA_010383 promoted proteinuria and renal fibrosis in DN by acting as a sponge for miRNA-135a. This study reveals that circRNA_010383 may be a novel therapeutic target for DN in the future.

Micheliolide Attenuates Lipopolysaccharide-Induced Inflammation by Modulating the mROS/NF-κB/NLRP3 Axis in Renal Tubular Epithelial Cells.

Chronic kidney disease is a common disease closely related to renal tubular inflammation and oxidative stress, and no effective treatment is available. Activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important factor in renal inflammation, but the mechanism remains unclear. Micheliolide (MCL), which is derived from parthenolide, is a new compound with antioxidative and anti-inflammatory effects and has multiple roles in tumors and inflammatory diseases. In this study, we investigated the effect of MCL on lipopolysaccharide- (LPS-) induced inflammation in renal tubular cells and the related mechanism. We found that MCL significantly suppressed the LPS-induced NF-κB signaling and inflammatory expression of cytokines, such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in a rat renal proximal tubular cell line (NRK-52E). MCL also prevented LPS- and adenosine triphosphate-induced NLRP3 inflammasome activation in vitro, as evidenced by the inhibition of NLRP3 expression, caspase-1 cleavage, and interleukin-1ß and interleukin-18 maturation and secretion. Additionally, MCL inhibited the reduction of mitochondrial membrane potential and decreases the release of reactive oxygen species (ROS). Moreover, MCL can prevent NLRP3 inflammasome activation induced by rotenone, a well-known mitochondrial ROS (mROS) agonist, indicating that the mechanism of MCL's anti-inflammatory effect may be closely related to the mROS. In conclusion, our study indicates that MCL can inhibit LPS-induced renal inflammation through suppressing the mROS/NF-κB/NLRP3 axis in tubular epithelial cells.