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.

Indigenized Characterization Factors for Health Damage Due to Ambient PM2.5 in Life Cycle Impact Assessment in China.

Life cycle assessment (LCA) is a broadly used method for quantifying environmental impacts, and life cycle impact assessment (LCIA) is an important step as well as a major source of uncertainties in LCA. Characterization factors (CFs) are pivotal elements in LCIA models. In China, the health loss due to ambient PM2.5 is an important aspect of LCIA results, which, however, is generally assessed by adopting CFs developed by global models and there remains a need to integrate localized considerations and the latest information for more precise applications in China. In this study, we developed indigenized CFs for LCIA of health damage due to ambient PM2.5 in China by coupling the atmospheric chemical transport model GEOS-Chem, exposure-response model GEMM containing Chinese cohort studies, and the latest local data. Results show that CFs of four major PM2.5 precursors all exhibit significant interregional variation and monthly differences in China. Our results were generally an order of magnitude higher and show disparate spatial distribution compared to CFs currently in use, suggesting that the health damage due to ambient PM2.5 was underestimated in LCIA in China, and indigenized CFs need to be adopted for more accurate results in LCIA and LCA studies.

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.

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.

FOXO3a accumulation and activation accelerate oxidative stress-induced podocyte injury.

Podocyte injury is the primary cause of glomerular injury in diabetic nephropathy (DN). Advanced oxidation protein products (AOPPs), the triggers and markers of oxidative stress in DN, have been linked to podocyte damage. However, the underlying mechanism is not yet clear. Here, we investigated the potential role of FOXO3a, a key transcription factor in the response to stress, in mediating AOPPs-induced podocyte injury. We found that FOXO3a expression was increased in the glomeruli of kidney biopsies from patients with DN and it was positively correlated with proteinuria. The serum from patients with DN significantly increased FOXO3a and its downstream genes FasL and Bim, thereby inducing the high level of cleaved caspase3 and the loss of nephrin and podocin expressions in podocytes. Blockade of AOPPs signaling by a neutralizing antibody against the receptor of advanced glycation end products (αRAGE) abolished the effect of DN serum on podocytes, confirming the pathogenic role of AOPPs in DN serum. Downregulation of FOXO3a decreased AOPPs-induced podocyte apoptosis and restored the levels of podocyte markers nephrin and podocin, and upregulation of FOXO3a exacerbated these changes in podocytes after AOPPs treatment. Furthermore, FOXO3a specifically activated proapoptotic genes in podocytes only in the presence of AOPPs. Mechanistically, AOPPs increased the FOXO3a protein levels by inhibiting their autophagic degradation in a ROS/mTOR-dependent manner. Moreover AOPPs activated the accumulated FOXO3a by maintaining FOXO3a in the nucleus, and this process was dependent on ROS-mediated AKT signaling deactivation. These studies suggest that FOXO3a plays a critical role in mediating AOPPs-induced podocyte injury and reveal a new mechanistic linkage of oxidative stress, FOXO3a activation and podocyte injury in DN.

MicroRNA-145 promotes the epithelial-mesenchymal transition in peritoneal dialysis-associated fibrosis by suppressing fibroblast growth factor 10.

Peritoneal fibrosis is a common complication of long-term peritoneal dialysis (PD) and the principal cause of ultrafiltration failure during PD. The initial and reversible step in PD-associated peritoneal fibrosis is the epithelial-mesenchymal transition (EMT). Although the mechanisms in the EMT have been the focus of many studies, only limited information is currently available concerning microRNA (miRNA) regulation in peritoneal fibrosis. In this study, we aimed to characterize the roles of microRNA-145 (miR-145) and fibroblast growth factor 10 (FGF10) in peritoneal fibrosis. After inducing EMT with transforming growth factor-ß1 (TGF-ß1) in vitro, we found that miR-145 is significantly up-regulated, whereas FGF10 is markedly down-regulated, suggesting a close link between miR-145 and FGF10 in peritoneal fibrosis, further confirmed in luciferase reporter experiments. Furthermore, in human peritoneal mesothelial cells (i.e. HMrSV5 cells), miR-145 mimics induced EMT, whereas miR-145 inhibition suppressed EMT, and we also observed that miR-145 suppressed FGF10 expression. In vivo, we found that the exogenous delivery of an miR-145 expression plasmid both blocked FGF10 and intensified the EMT, whereas miR-145 inhibition promoted the expression of FGF10 and reversed the EMT. In conclusion, miR-145 promotes the EMT during the development of peritoneal fibrosis by suppressing FGF10 activity, suggesting that miR-145 represents a potential therapeutic target for managing peritoneal fibrosis.

Correction: Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.

Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for in vivo use, in two renal fibrosis models-the unilateral ureteral occlusion (UUO) model and an ischaemia-reperfusion injury (IRI) model and used MCL in combination with transforming growth factor beta 1 (TGF-ß1) on mouse tubular epithelial cells (mTEC) in vitro. The expression of fibrotic markers (fibronectin and α-SMA) was remarkably reduced, while the expression of the epithelial marker E-cadherin was restored after DMAMCL treatment both in the UUO and IRI mice. MCL function in TGF-ß1-induced epithelial-mesenchymal transition (EMT) in mTEC was consistent with the in vivo results. Metadherin (Mtdh) was activated in the fibrotic condition, suggesting that it might be involved in fibrogenesis. Interestingly, we found that while Mtdh was upregulated in the fibrotic condition, DMAMCL/MCL could suppress its expression. The overexpression of Mtdh exerted a pro-fibrotic effect by modulating the BMP/MAPK pathway in mTECs, and MCL could specifically reverse this effect. In conclusion, DMAMCL/MCL treatment represents a novel and effective therapy for renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.

Tenascin-C protects against acute kidney injury by recruiting Wnt ligands.

The development of acute kidney injury (AKI) is a complex process involving tubular, inflammatory, and vascular components, but less is known about the role of the interstitial microenvironment. We have previously shown that the extracellular matrix glycoprotein tenascin-C (TNC) is induced in fibrotic kidneys. In mouse models of AKI induced by ischemia-reperfusion injury (IRI) or cisplatin, TNC was induced de novo in the injured sites and localized to the renal interstitium. The circulating level of TNC protein was also elevated in AKI patients after cardiac surgery. Knockdown of TNC by shRNA in vivo aggravated AKI after ischemic or toxic injury. This effect was associated with reduced renal ß-catenin expression, suggesting an impact on Wnt signaling. In vitro, TNC protected tubular epithelial cells against apoptosis and augmented Wnt1-mediated ß-catenin activation. Co-immunoprecipitation revealed that TNC physically interacts with Wnt ligands. Furthermore, a TNC-enriched kidney tissue scaffold prepared from IRI mice was able to recruit and concentrate Wnt ligands from the surrounding milieu ex vivo. The ability to recruit Wnt ligands in this ex vivo model diminished after TNC depletion. These studies indicate that TNC is specifically induced at sites of injury and recruits Wnt ligands, thereby creating a favorable microenvironment for tubular repair and regeneration after AKI.

Micheliolide ameliorates diabetic kidney disease by inhibiting Mtdh-mediated renal inflammation in type 2 diabetic db/db mice.

Diabetic kidney disease (DKD) is the principal cause of end-stage renal disease worldwide and few treatments are available. Because immunomodulators are pivotal to DKD pathophysiology, anti-inflammatory agents may be useful for treating DKD. This study was conducted to investigate the effect of micheliolide (MCL), a novel guaianolide sesquiterpene lactone with well-known anti-inflammatory effects, on DKD. Treatment with dimethylaminomicheliolide (DMAMCL), the pro-drug of MCL currently under clinical trial in oncology, protected the kidneys against proteinuria, renal failure, histopathological injury, and inflammation in db/db mice. This effect was associated with metadherin (Mtdh) downregulation. We observed aberrant upregulation of Mtdh in the kidneys of db/db mice and high-glucose (HG)-induced mouse tubular epithelial cells (mTECs). Downregulation of Mtdh obviously inhibited nuclear factor-κB signaling activation and suppressed its downstream inflammatory cytokines, such as monocyte chemotactic peptide-1, interleukin-1ß, tumor necrosis factor-α, and interleukin-6 in HG-induced mTECs, which was similar to the effect of MCL. Mtdh overexpression largely reversed the anti-inflammatory role of MCL. Moreover, MCL downregulated Mtdh by both inhibiting the transcription level and promoting ubiquitin-mediated degradation. These findings suggest that DMAMCL is a promising anti-inflammatory agent useful for preventing renal injury in DKD by inhibiting Mtdh-mediated renal inflammation.

Carbon Materials Inhibit Formation of Nitrated Aromatic Products in Treatment of Phenolic Compounds by Thermal Activation of Peroxydisulfate in the Presence of Nitrite.

Recent studies have reported that toxic nitrated aromatic products are generated during treatment of phenolic compounds by thermally activated peroxydisulfate (thermal/PDS) in the presence of nitrite (NO2-). This work explored the potential of carbon materials on controlling the formation of nitrated aromatic products using phenol as a model compound. In the presence of selected carbon materials including diverse carbon nanotubes (CNT) and powdered activated carbon (PAC), the transformation kinetics of phenol was significantly enhanced, primarily attributed to nonradical activation of PDS by carbon materials. Nitrophenols (NPs) including 2-NP and 4-NP were formed in phenol oxidation by the thermal/PDS/NO2- process, due to the reaction of phenol with reactive nitrogen species generated from NO2- oxidation. The addition of carbon materials obviously inhibited NPs formation under various experimental conditions. The bonding of nitro groups on the CNT surface was clearly confirmed by means of various characterizations, probably resulting from the competitive reaction of reactive nitrogen species with CNT vs phenol. The controlling effect of carbon materials was also verified in the cases of other phenolic compounds. Therefore, the addition of carbon materials may be a promising approach to control the formation of undesirable nitrated byproducts by the thermal/PDS process in the presence of NO2-.

Wnt9a Promotes Renal Fibrosis by Accelerating Cellular Senescence in Tubular Epithelial Cells.

Cellular senescence is associated with renal disease progression, and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. However, the underlying mechanism is unknown. We assessed the potential role of Wnt9a in tubular cell senescence and renal fibrosis. Compared with tubular cells of normal subjects, tubular cells of humans with a variety of nephropathies and those of several mouse models of CKD expressed high levels of Wnt9a that colocalized with the senescence-related protein p16INK4A Wnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and expression of p16INK4A Furthermore, ectopic expression of Wnt9a after ischemia-reperfusion injury (IRI) induced activation of ß-catenin and exacerbated renal fibrosis. Overexpression of Wnt9a exacerbated tubular senescence, evidenced by increased detection of p16INK4A expression and senescence-associated ß-galactosidase activity. Conversely, shRNA-mediated knockdown of Wnt9a repressed IRI-induced renal fibrosis in vivo and impeded the growth of senescent tubular epithelial cells in culture. Notably, Wnt9a-induced renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4A in the IRI mouse model. In a human proximal tubular epithelial cell line and primary renal tubular cells, Wnt9a remarkably upregulated levels of senescence-related p16INK4A, p19ARF, p53, and p21 and decreased the phosphorylation of retinoblastoma protein. Wnt9a also induced senescent tubular cells to produce TGF-ß1, which promoted proliferation and activation in normal rat kidney fibroblasts. Thus, Wnt9a drives tubular senescence and fibroblast activation. Furthermore, the Wnt9a-TGF-ß pathway appears to create a reciprocal activation loop between senescent tubular cells and activated fibroblasts that promotes and accelerates the pathogenesis of renal fibrosis.

Oxidation Kinetics of Bromophenols by Nonradical Activation of Peroxydisulfate in the Presence of Carbon Nanotube and Formation of Brominated Polymeric Products.

This work demonstrated that bromophenols (BrPs) could be readily oxidized by peroxydisulfate (PDS) activated by a commercial carbon nanotube (CNT), while furfuryl alcohol (a chemical probe for singlet oxygen (1O2)) was quite refractory. Results obtained by radical quenching experiments, electron paramagnetic resonance spectroscopy, and Fourier transform infrared spectroscopy further confirmed the involvement of nonradical PDS-CNT complexes rather than 1O2. Bicarbonate and chloride ion exhibited negligible impacts on BrPs degradation by the PDS/CNT system, while a significant inhibitory effect was observed for natural organic matter. The oxidation of BrPs was influenced by solution pH with maximum rates occurring at neutral pH. Linear free energy relationships (LFERs) were established between the observed pseudo-first-order oxidation rates of various substituted phenols and the classical descriptor variables (i.e., Hammett constant σ+, and half-wave oxidation potential E1/2). Products analyses by liquid chromatography tandem mass spectrometry clearly showed the formation of hydroxylated polybrominated diphenyl ethers and hydroxylated polybrominated biphenyls on CNT surface. Their formation pathway possibly involved the generation of bromophenoxyl radicals from BrPs one-electron oxidation and their subsequent coupling reactions. These results suggest that the novel nonradical PDS/CNT oxidation technology is a good alternative for selectively eliminating BrPs with alleviating toxic byproducts in treated water effluent.

Transformation of Iodide by Carbon Nanotube Activated Peroxydisulfate and Formation of Iodoorganic Compounds in the Presence of Natural Organic Matter.

In this study, we interestingly found that peroxydisulfate (PDS) could be activated by a commercial multiwalled carbon nanotube (CNT) material via a nonradical pathway. Iodide (I-) was quickly and almost completely oxidized to hypoiodous acid (HOI) in the PDS/CNT system over the pH range of 5-9, but the further transformation to iodate (IO3-) was negligible. A kinetic model was proposed, which involved the formation of reactive PDS-CNT complexes, and then their decomposition into sulfate anion (SO42-) via inner electron transfer within the complexes or by competitively reacting with I-. Several influencing factors (e.g., PDS and CNT dosages, and solution pH) on I- oxidation kinetics by this system were evaluated. Humic acid (HA) decreased the oxidation kinetics of I-, probably resulting from its inhibitory effect on the interaction between PDS and CNT to form the reactive complexes. Moreover, adsordable organic iodine compounds (AOI) as well as specific iodoform and iodoacetic acid were appreciably produced in the PDS/CNT/I- system with HA. These results demonstrate the potential risk of producing toxic iodinated organic compounds in the novel PDS/CNT oxidation process developed very recently, which should be taken into consideration before its practical application in water treatment.

ABTS as an Electron Shuttle to Enhance the Oxidation Kinetics of Substituted Phenols by Aqueous Permanganate.

In this study, it was, interestingly, found that 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulfonate (ABTS), a widely used electron shuttle, could greatly accelerate the oxidation of substituted phenols by potassium permanganate (Mn(VII)) in aqueous solutions at pH 5-9. This was attributed to the fact that these substituted phenols could be readily oxidized by the stable radical cation (ABTS(•+)), which was quickly produced from the oxidation of ABTS by Mn(VII). The reaction of Mn(VII) with ABTS exhibited second-order kinetics, with stoichiometries of ∼5:1 at pH 5-6 and ∼3:1 at pH 7-9, and the rate constants varied negligibly from pH 5 to 9 (k = (9.44 ± 0.21) × 10(4) M(-1) s(-1)). Comparatively, the reaction of ABTS(•+) with phenol showed biphasic kinetics. The second-order rate constants for the reactions of ABTS(•+) with substituted phenols obtained in the initial phase were strongly affected by pH, and they were several orders of magnitude higher than those for the reactions of Mn(VII) with substituted phenols at each pH. Good Hammett-type correlations were found for the reactions of ABTS(•+) with undissociated (log(k) = 2.82-4.31σ) and dissociated phenols (log(k) = 7.29-5.90σ). The stoichiometries of (2.2 ± 0.06):1 (ABTS(•+) in excess) and (1.38 ± 0.18):1 (phenol in excess) were achieved in the reaction of ABTS(•+) with phenol, but they exhibited no pH dependency.

IGF2BP3/NCBP1 complex inhibits renal tubular senescence through regulation of CDK6 mRNA stability.

Renal aging and the subsequent rise in kidney-related diseases are attributed to senescence in renal tubular epithelial cells (RTECs). Our study revealed that the abnormal expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of RNA N6-methyladenosine, is critically involved in cisplatin-induced renal tubular senescence. In cisplatin-induced senescence of RTECs, the promoter activity and transcription of IGF2BP3 is markedly suppressed. It was due to the down regulation of MYC proto-oncogene (MYC), which regulates IGF2BP3 transcription by binding to the putative site at 1852-1863 of the IGF2BP3 promoter. Overexpression of IGF2BP3 ameliorated cisplatin-induced renal tubular senescence in vitro. Mechanistic studies revealed that IGF2BP3 inhibits cellular senescence in RTECs by enhancing cyclin-dependent kinase 6 (CDK6) mRNA stability and increasing its expression. The inhibition effect of IGF2BP3 on tubular senescence is partially reversed by the knockdown of CDK6. Further, IGF2BP3 recruits nuclear cap binding protein subunit 1 (NCBP1) and inhibits CDK6 mRNA decay, by recognizing m6A modification. Specifically, IGF2BP3 recognizes m6A motif "GGACU" at nucleotides 110-114 in the 5' untranslated region (UTR) field of CDK6 mRNA. The involvement of IGF2BP3/CDK6 in alleviating tubular senescence was confirmed in a cisplatin-induced acute kidney injury (AKI)-to-chronic kidney disease (CKD) model. Clinical data also suggests an age-related decrease in IGF2BP3 and CDK6 levels in renal tissue or serum samples from patients. These findings suggest that IGF2BP3/CDK6 may be a promising target in cisplatin-induced tubular senescence and renal failure.

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.

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.

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.