Roxadustat Versus Erythropoietin: The Comparison of Efficacy in Reversing Ventricular Remodeling in Dialysis Patients with Anaemia.

Background: Renal anaemia and left ventricular hypertrophy are the main complications of chronic kidney disease and are shared among dialysis patients. This retrospective study aimed to compare the efficacies of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat and recombinant human erythropoietin in reversing ventricular remodeling in dialysis patients with renal anaemia. Methods: A total of 204 participants underwent baseline examinations, including echocardiograms and laboratory tests, before being administered either treatment for at least 24 weeks from January 2018 to October 2021, after which follow-up examinations were conducted at 6 months. Propensity score matching based on key variables included age, gender, cardiovascular diseases, cardiovascular medications, dialysis course and the vascular access at baseline was performed to include populations with similar characteristics between groups. Results: In total, 136 patients were included with roxadustat or recombinant human erythropoietin. The left ventricular mass index after treatment with roxadustat and recombinant human erythropoietin both significantly decreased after 6 months, but there was no significant difference in the change in left ventricular mass index between the two groups. In addition, the left ventricular end-diastolic diameters and left ventricular wall thickness, systolic blood pressure, and diastolic blood pressure significantly decreased in the roxadustat group. Roxadustat and recombinant human erythropoietin also increased haemoglobin significantly, but there was no significant difference in the change in haemoglobin between the two groups. The results of multiple linear regression showed that the change in haemoglobin was independent factor affecting the improvement of left ventricular mass index. Conclusions: The increase of haemoglobin was associated with improving left ventricular hypertrophy in dialysis patients. However, the beneficial effects between roxadustat and recombinant human erythropoietin on left ventricular mass index did not show clear superiority or inferiority in six months.

Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway.

Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to disease progression. Abnormal glucose metabolism disrupts renal lipid metabolism, leading to lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial inflammation. In this study, we investigated the mechanisms underlying the renal inflammation in diabetes, driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2 (ACSS2) in lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1ß in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced inflammation, mitochondrial stress, and fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with Sirtuin 1 (SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN. Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.

The ratio of neutrophils to lymphocytes effectively predicts clinical outcomes in idiopathic membranous nephropathy.

BACKGROUND: Systemic inflammatory indicators are important in the prognoses of various diseases. Such indicators, including the neutrophil-to-lymphocyte ratio (NLR), can be meaningful in predicting the clinical outcome in patients diagnosed with idiopathic membranous nephropathy (IMN). MATERIALS AND METHODS: 112 IMN patients diagnosed by renal biopsy were recruited retrospectively. The endpoint was defined as a combination of partial and complete remission. Statistical analysis determined the independent factors associated with clinical remission and the predictive utility of NLR. RESULTS: Within the 12-month follow-up period, 72 patients achieved clinical remission after treatment. Univariate analysis identified significant differences in serum albumin, estimated glomerular filtration rate (eGFR), proteinuria, neutrophil count, and NLR between the remission group and the non-remission group (all p < 0.05). Cox proportional hazards indicated that elevated eGFR (HR 1.022, 95% CI (1.009 - 1.035), p = 0.001), lower NLR (HR 0.345, 95% CI (0.237 - 0.501), p = 0.0001), and decreased proteinuria (HR 0.826, 95% CI (0.693 - 0.984), p = 0.032) were protective elements for remission. With an optimal cut-off value of 2.61, the pre-treatment NLR had an excellent ability to identify the remission (area under the curve (AUC), 0.785). Participants were separated into low- and high-NLR groups by using 2.61. Kaplan-Meier survival curves revealed significantly higher remission rates in the lower group (p < 0.0001). CONCLUSION: The NLR is an effective indicator for predicting clinical remission in patients with IMN.

Activation of acetyl-CoA synthetase 2 mediates kidney injury in diabetic nephropathy.

Albuminuria and podocyte injury are the key cellular events in the progression of diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is a nucleocytosolic enzyme responsible for the regulation of metabolic homeostasis in mammalian cells. This study aimed to investigate the possible roles of ACSS2 in kidney injury in DN. We constructed an ACSS2-deleted mouse model to investigate the role of ACSS2 in podocyte dysfunction and kidney injury in diabetic mouse models. In vitro, podocytes were chosen and transfected with ACSS2 siRNA and ACSS2 inhibitor and treated with high glucose. We found that ACSS2 expression was significantly elevated in the podocytes of patients with DN and diabetic mice. ACSS2 upregulation promoted phenotype transformation and inflammatory cytokine expression while inhibiting podocytes' autophagy. Conversely, ACSS2 inhibition improved autophagy and alleviated podocyte injury. Furthermore, ACSS2 epigenetically activated raptor expression by histone H3K9 acetylation, promoting activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Pharmacological inhibition or genetic depletion of ACSS2 in the streptozotocin-induced diabetic mouse model greatly ameliorated kidney injury and podocyte dysfunction. To conclude, ACSS2 activation promoted podocyte injury in DN by raptor/mTORC1-mediated autophagy inhibition.

Outer membrane vesicles derived from gut microbiota mediate tubulointerstitial inflammation: a potential new mechanism for diabetic kidney disease.

Rationale: Chronic tubulointerstitial inflammation is a common pathological process in diabetic kidney disease (DKD). However, its underlying mechanism is largely unknown. This study aims at investigating the role of gut microbiota-derived outer membrane vesicles (OMVs) in tubulointerstitial inflammation in DKD. Methods: Gut microbiota in diabetes mellitus rats was manipulated by microbiota depletion and fecal microbiota transplantation to explore its role in tubulointerstitial inflammation. To check the direct effects of OMVs, fecal bacterial extracellular vesicles (fBEVs) were administrated to mice orally and HK-2 cells in vitro. For mechanistic investigations, HK-2 cells were treated with small interfering RNA against caspase-4 and fBEVs pre-neutralized by polymyxin B. Results: By performing gut microbiota manipulation, it was confirmed that gut microbiota mediated tubulointerstitial inflammation in DKD. In diabetic rats, gut microbiota-derived OMVs were increased and were clearly detected in distant renal tubulointerstitium. Diabetic fBEVs directly administered by gavage translocated into tubular epithelial cells and induced tubulointerstitial inflammation and kidney injury. In vitro, OMVs were internalized through various endocytic pathways and triggered cellular inflammatory response. Mechanistically, it was revealed that OMVs-derived lipopolysaccharide induced tubular inflammation, which was mediated by the activation of the caspase-11 pathway. Conclusions: Increased OMVs due to dysbiosis translocated through leaky gut barrier into distant tubulointerstitium and induced cellular inflammation and renal tubulointerstitial injury in DKD. These findings enrich the mechanism understanding of how gut microbiota and its releasing OMVs influence the development and progression of kidney disease.

Activation of HIF-1α C-terminal transactivation domain protects against hypoxia-induced kidney injury through hexokinase 2-mediated mitophagy.

The transcription factor hypoxia-inducible factor-1α (HIF-1α), as a master regulator of adaptive responses to hypoxia, possesses two transcriptional activation domains [TAD, N-terminal (NTAD), and C-terminal (CTAD)]. Although the roles of HIF-1α NTAD in kidney diseases have been recognized, the exact effects of HIF-1α CTAD in kidney diseases are poorly understood. Here, two independent mouse models of hypoxia-induced kidney injury were established using HIF-1α CTAD knockout (HIF-1α CTAD-/-) mice. Furthermore, hexokinase 2 (HK2) and mitophagy pathway are modulated using genetic and pharmacological methods, respectively. We demonstrated that HIF-1α CTAD-/- aggravated kidney injury in two independent mouse models of hypoxia-induced kidney injury, including ischemia/reperfusion-induced kidney injury and unilateral ureteral obstruction-induced nephropathy. Mechanistically, we found that HIF-1α CTAD could transcriptionally regulate HK2 and subsequently ameliorate hypoxia-induced tubule injury. Furthermore, it was found that HK2 deficiency contributed to severe renal injury through mitophagy inhibition, while mitophagy activation using urolithin A could significantly protect against hypoxia-induced kidney injury in HIF-1α C-TAD-/- mice. Our findings suggested that the HIF-1α CTAD-HK2 pathway represents a novel mechanism of kidney response to hypoxia, which provides a promising therapeutic strategy for hypoxia-induced kidney injury.

Loss of Sirt1 promotes exosome secretion from podocytes by inhibiting lysosomal acidification in diabetic nephropathy.

Podocyte injury is a characteristic feature of diabetic nephropathy (DN). The secretion of exosomes in podocytes increases significantly in DN; however, the precise mechanisms remain poorly understood. Here, we demonstrated that Sirtuin1 (Sirt1) was significantly downregulated in podocytes in DN, which correlated negatively with increased exosome secretion. Similar results were observed in vitro. We found that lysosomal acidification in podocytes following high glucose administration was markedly inhibited, resulting in the decreased lysosomal degradation of multivesicular bodies. Mechanistically, we indicated that loss of Sirt1 contributed to the inhibited lysosomal acidification by decreasing the expression of the A subunit of the lysosomal vacuolar-type H+ ATPase proton pump (ATP6V1A) in podocytes. Overexpression of Sirt1 significantly improved lysosomal acidification with increased expression of ATP6V1A and inhibited exosome secretion. These findings suggest that dysfunctional Sirt1-mediated lysosomal acidification is the exact mechanism of increased secretion of exosomes in podocytes in DN, providing insights into potential therapeutic strategies for preventing DN progression.

Deposition of platelet-derived microparticles in podocytes contributes to diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world. Podocyte injury is a critical cellular event involved in the progression of DN. Our previous studies demonstrated that platelet-derived microparticles (PMPs) mediated endothelial injury in diabetic rats. This study aimed to investigate whether PMPs are deposited in podocytes and to assess their potential effects on podocyte injury in DN. METHODS: The deposition of PMPs in podocytes was assessed by immunofluorescent staining and electron microscopy. The changes in renal pathology and ultra-microstructure were assessed by periodic acid-Schiff staining and electron microscopy, respectively. The expression of inflammatory cytokines and extracellular matrix proteins was measured by immuno-histochemical staining and western blot. RESULTS: PMPs were widely deposited in podocytes of glomeruli in diabetic patients and animal models and closely associated with DN progression. Interestingly, aspirin treatment significantly inhibited the accumulation of PMPs in the glomeruli of diabetic rats, alleviated mesangial matrix expansion and fusion of foot processes, and decreased the protein expression of inflammatory cytokines and extracellular matrix secretion. An in vitro study further confirmed the deposition of PMPs in podocytes. Moreover, PMP stimulation induced the phenotypic transition of podocytes through decreased podocin protein expression and increased protein expression of α-SMA and fibronectin, which was correlated with increased production of inflammatory cytokines. CONCLUSION: Our findings demonstrated for the first time that the deposition of PMPs in podocytes contributed to the development of DN.

GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway.

Background: G-protein-coupled receptor 43 (GPR43) is a posttranscriptional regulator involved in cholesterol metabolism. This study aimed to investigate the possible roles of GPR43 activation in podocyte lipotoxicity in diabetic nephropathy (DN) and explore the potential mechanisms. Methods: The experiments were conducted by using diabetic GPR43-knockout mice and a podocyte cell culture model. Lipid deposition and free cholesterol levels in kidney tissues were measured by BODIPY staining and quantitative cholesterol assays, respectively. The protein expression of GPR43, LC3II, p62, beclin1, low-density lipoprotein receptor (LDLR) and early growth response protein 1 (EGR1) in kidney tissues and podocytes was measured by real-time PCR, immunofluorescent staining and Western blotting. Results: There were increased LDL cholesterol levels in plasma and cholesterol accumulation in the kidneys of diabetic mice. However, GPR43 gene knockout inhibited these changes. An in vitro study further demonstrated that acetate treatment induced cholesterol accumulation in high glucose-stimulated podocytes, which was correlated with increased cholesterol uptake mediated by LDLR and reduced cholesterol autophagic degradation, as characterized by the inhibition of LC3 maturation, p62 degradation and autophagosome formation. Gene knockdown or pharmacological inhibition of GPR43 prevented these effects on podocytes. Furthermore, GPR43 activation increased extracellular regulated protein kinases 1/2 (ERK1/2) activity and EGR1 expression in podocytes, which resulted in an increase in cholesterol influx and autophagy inhibition. In contrast, after GPR43 deletion, these changes in podocytes were improved, as shown by the in vivo and in vitro results. Conclusion: GPR43 activation-mediated lipotoxicity contributes to podocyte injury in DN by modulating the ERK/EGR1 pathway.

Effects of Sacubitril/Valsartan on resistant hypertension and myocardial work in hemodialysis patients.

Growing evidences have confirmed the effect of Sacubitril/Valsartan (SV) on antihypertension and cardiac protection in general population. However, there was no prospective study about the effect and safety of SV on resistant hypertension and myocardial work in hemodialysis patients. In this single-center, prospective, before-after study, enrolled patients were endured with resistant hypertension for more than 6 months. Participants were initially instructed to take SV 50 mg twice daily, and the dosage was gradually increased up to 100 mg twice daily. The primary outcomes were blood pressure (BP) control, N-terminal pro-B-type natriuretic peptide (NT-proBNP), myocardial work (MW), fatigue and life quality. In addition, the adverse events were also recorded in this cohort. A total of 18 patients (34-64 years old) was finally enrolled and completed in this study. The SV-based regimen provided significantly mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-20.7/-8.3 mm Hg), respectively. The cardiac remodeling parameters were partially improved. Compared to the baseline, NT-proBNP was significantly reduced at week 4 (8119.50 [3710.75, 29300] pg/ml to 7216.50 [4124.75, 17455.00] pg/ml, p = .046), which was much lower at week 12 (3130.50 [2244.50, 9565.70] pg/ml, p = .037). Global MW index was higher at week 12 compared to the baseline (p = .026). MW efficiency was also improved accordingly compared to the baseline, even though the statistical difference was not significant (p = .226). Life quality and fatigue were improved at week 12 compared to the baseline (all p = .000). There was no serious adverse events were observed. SV safely and effectively controlled resistant hypertension and improved MW as well as life quality in hemodialysis patients.

EphA8 inhibits cell apoptosis via AKT signaling and is associated with poor prognosis in breast cancer.

Erythropoietin­producing hepatocellular receptors (Ephs) comprise the largest subfamily of receptor tyrosine kinases and have been reported to be involved in a variety of biological cellular processes, including tumorigenesis and cancer progression. The present study aimed to determine the expression levels and clinicopathological significance of EphA8 in breast cancer (BC) using immunohistochemistry analysis of tissue microarrays. The results of the present study revealed that EphA8 expression levels were upregulated in BC tissue and were associated with tumor size and TNM stage. In addition, upregulated expression levels of EphA8 were identified to be a poor prognostic biomarker for patients with BC. The knockdown of EphA8 expression using short hairpin RNA resulted in increased levels of apoptosis as well as decreased proliferation, migration and invasion of BC cells both in vivo and in vitro. The knockdown of EphA8 also decreased the phosphorylation of AKT, which was accompanied by downregulation of Bcl­2 expression levels and upregulation of p53, Caspase­3 and Bax expression levels. Moreover, knockdown of EphA8 expression increased the chemosensitivity of BC cells to paclitaxel. In conclusion, the results of the present study indicated that EphA8 may be a useful prognostic marker in BC and that knockdown of EphA8 may represent a novel strategy in adjuvant chemotherapy for the treatment of BC.

GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKα activity.

Rationale: Albuminuria is an early clinical feature in the progression of diabetic nephropathy (DN). Podocyte insulin resistance is a main cause of podocyte injury, playing crucial roles by contributing to albuminuria in early DN. G protein-coupled receptor 43 (GPR43) is a metabolite sensor modulating the cell signalling pathways to maintain metabolic homeostasis. However, the roles of GPR43 in podocyte insulin resistance and its potential mechanisms in the development of DN are unclear. Methods: The experiments were conducted by using kidney tissues from biopsied DN patients, streptozotocin (STZ) induced diabetic mice with or without global GPR43 gene knockout, diabetic rats treated with broad-spectrum oral antibiotics or fecal microbiota transplantation, and cell culture model of podocytes. Renal pathological injuries were evaluated by periodic acid-schiff staining and transmission electron microscopy. The expression of GPR43 with other podocyte insulin resistance related molecules was checked by immunofluorescent staining, real-time PCR, and Western blotting. Serum acetate level was examined by gas chromatographic analysis. The distribution of gut microbiota was measured by 16S ribosomal DNA sequencing with faeces. Results: Our results demonstrated that GPR43 expression was increased in kidney samples of DN patients, diabetic animal models, and high glucose-stimulated podocytes. Interestingly, deletion of GPR43 alleviated albuminuria and renal injury in diabetic mice. Pharmacological inhibition and knockdown of GPR43 expression in podocytes increased insulin-induced Akt phosphorylation through the restoration of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) activity. This effect was associated with the suppression of AMPKα activity through post-transcriptional phosphorylation via the protein kinase C-phospholipase C (PKC-PLC) pathway. Antibiotic treatment-mediated gut microbiota depletion, and faecal microbiota transplantation from the healthy donor controls substantially improved podocyte insulin sensitivity and attenuated glomerular injury in diabetic rats accompanied by the downregulation of the GPR43 expression and a decrease in the level of serum acetate. Conclusion: These findings suggested that dysbiosis of gut microbiota-modulated GPR43 activation contributed to albuminuria in DN, which could be mediated by podocyte insulin resistance through the inhibition of AMPKα activity.

Using Machine Learning to Evaluate the Role of Microinflammation in Cardiovascular Events in Patients With Chronic Kidney Disease.

Background: Lipid metabolism disorder, as one major complication in patients with chronic kidney disease (CKD), is tied to an increased risk for cardiovascular disease (CVD). Traditional lipid-lowering statins have been found to have limited benefit for the final CVD outcome of CKD patients. Therefore, the purpose of this study was to investigate the effect of microinflammation on CVD in statin-treated CKD patients. Methods: We retrospectively analysed statin-treated CKD patients from January 2013 to September 2020. Machine learning algorithms were employed to develop models of low-density lipoprotein (LDL) levels and CVD indices. A fivefold cross-validation method was employed against the problem of overfitting. The accuracy and area under the receiver operating characteristic (ROC) curve (AUC) were acquired for evaluation. The Gini impurity index of the predictors for the random forest (RF) model was ranked to perform an analysis of importance. Results: The RF algorithm performed best for both the LDL and CVD models, with accuracies of 82.27% and 74.15%, respectively, and is therefore the most suitable method for clinical data processing. The Gini impurity ranking of the LDL model revealed that hypersensitive C-reactive protein (hs-CRP) was highly relevant, whereas statin use and sex had the least important effects on the outcomes of both the LDL and CVD models. hs-CRP was the strongest predictor of CVD events. Conclusion: Microinflammation is closely associated with potential CVD events in CKD patients, suggesting that therapeutic strategies against microinflammation should be implemented to prevent CVD events in CKD patients treated by statin.

Plasma levels of ceramides relate to ischemic stroke risk and clinical severity.

Recent studies have suggested that specific plasma ceramides are independently associated with atherosclerosis and cardiovascular diseases, but it is currently unknown whether plasma ceramide levels are associated with ischemic stroke. Here, we examined whether ceramides were associated with both ischemic stroke risk and clinical severity at admission. We measured three previously identified high-risk plasma ceramide molecules [Cer(d18:1/16:0), Cer(d18:1/22:0), and Cer(d18:1/24:0)] in 202 patients with acute ischemic stroke and 202 age and sex matched control cases. Plasma ceramides levels were measured by a targeted liquid chromatography-tandem mass spectrometry assay at baseline. The median age of the 202 stroke patients was 66 (interquartile range [IQR], 58-75) years and 54.0 % were men. Plasma levels of C16:0, C22:0, and C24:0 ceramides in stroke patients were significantly higher than in those control cases (P < 0.001, all). In multivariate logistic regression analysis adjusted for other risk factors, higher levels of C16:0, C22:0, and C24:0 ceramides were associated with higher risk of ischemic stroke (odd ratio [OR] for one IQR increase: 2.15[1.42-2.99]; 2.90[2.13-4.01] and 1.29[1.10-1.69]; respectively). At admission, 103 patients (51.0 %) had a minor stroke (NIHSS < 6). In these patients, plasma levels of C16:0, C22:0, and C24:0 ceramides were lower than that observed in patients with moderate-to-high clinical severity (P < 0.001, all). In multivariate logistic regression analysis adjusted for other risk factors, higher levels of C16:0, C22:0, and C24:0 ceramides were associated with higher risk of moderate-to-high stroke (OR for one IQR increase: 2.96 [2.05-4.22], 3.03 [2.01-4.25] and 1.72 [1.25-3.31], respectively). An elevated plasma levels of ceramides were predictors of both risk and severity at admission in ischemic stroke patients. The underlying mechanisms of these associations remain to be investigated.

X-rays induced IL-8 production in lung cancer cells via p38/MAPK and NF-κB pathway.

PURPOSE: It is reported inflammatory cytokine interleukin-8 (IL-8) could predict radiation-induced lung toxicity (RILT). RILT is believed to be a consequence of a cascade of cytokine production. It is considered that vascular endothelial cell and macrophages are the mainly source of cytokines. This study was investigated the production of IL-8 from cancer cells induced by X-rays may involve in the radiation-induced inflammation. MATERIALS AND METHODS: We analyzed IL-8 in human lung cancer cell lines after expose to X-rays, and we also detect IL-8 in HUVEC cells and THP1 cells as endothelial cell and macrophage model to identify the change in normal cells after expose. Furthermore, we added the inhibitors to the culture with or without radiation to identify the role of MAPK and NF-κB pathways on the radiation-induced secretion of IL-8. RESULTS: Radiation could induce IL-8 production both in non-lung cancer cells (HUVECs and THP1 cells) and in lung cancer cells (A549 cells, H446 cells, PC-9 cells). Simultaneously, radiation activated p38/MAPK and NF-κB signal pathways in lung cancer cells. Moreover, p38/MAPK inhibitor SB203580 and NF-κB inhibitor BAY11-7082 could block the IL-8 up-regulated by X-rays but JNK inhibitor SP600125, ERK inhibitor U0126, ROS Scavenger NAC could not inhibit this phenomenon. CONCLUSIONS: X-rays could induce IL-8 production in lung cancer cells, which may be related to the activation of p38/MAPK and NF-κB signaling pathway, providing a new point for elucidating the mechanism of radiation pneumonitis.

Role of Podocyte Injury in Glomerulosclerosis.

Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes are prone to injuries; moreover, as a cell without proliferative potential, loss of podocytes is vital in the pathogenesis of glomerulosclerosis. Thus, sufficient understanding of factors and underlying mechanisms of podocyte injury facilitates the advancement of treating and prevention of glomerulosclerosis. The clinical symptom of podocyte injury is proteinuria, sometimes with loss of kidney functions progressing to glomerulosclerosis. Injury-induced changes in podocyte physiology and function are actually not a simple passive process, but a complex interaction of proteins that comprise the anatomical structure of podocytes at molecular levels. This chapter lists several aspects of podocyte injuries along with potential mechanisms, including glucose and lipid metabolism disorder, hypertension, RAS activation, micro-inflammation, immune disorder, and other factors. These aspects are not technically separated items, but intertwined with each other in the pathogenesis of podocyte injuries.

Publisher Correction: Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy.

The REFERENCES 1-35 are wrong because of the error in the process of typesetting.

Acid-Sensing Ion Channel 1a Modulates NMDA Receptor Function Through Targeting NR1/NR2A/NR2B Triheteromeric Receptors.

The over-activation of N-methyl-D-aspartate receptors (NMDARs) is the main cause of neuronal death in brain ischemia. Both the NMDAR and the Acid-sensing ion channel 1a (ASIC1a) are present in the postsynaptic membrane of the central nervous system (CNS) and participate in physiological and pathological processes. However, the specific role played by ASIC1a in these processes remains elusive. We hypothesize that NMDARs are the primary mediators of normal synaptic transmission and excitatory neuronal death, while ASIC1a plays a modulatory role in facilitating NMDAR function. Using various experimental approaches including patch-clamp recordings on hippocampal slices and CHO cells, primary cultures of hippocampal neurons, calcium imaging, Western blot, cDNA transfection studies, and transient middle cerebral artery occlusion (tMCAO) mouse models, we demonstrate that stimulation of ASIC1a facilitates NMDAR function and inhibition of ASIC1a suppresses NMDAR over-activation. One of our key findings is that activation of ASIC1a selectively facilitates the NR1/NR2A/NR2B triheteromeric subtype of NMDAR currents. In accordance, inhibition of ASIC1a profoundly reduced the NMDAR-mediated EPSCs in older mouse brains, which are known to express much higher levels of triheteromeric NMDARs than younger brains. Furthermore, brain infarct sizes were reduced by a greater degree in older mice compared to younger ones when ASIC1a activity was suppressed. These data suggest that ASIC1a activity selectively enhances the function of triheteromeric NMDARs and exacerbates ischemic neuronal death especially in older animal brains. We propose ASIC1a as a novel therapeutic target for preventing and reducing the detrimental effect of brain ischemia in humans.

Caspase 3/ROCK1 pathway mediates high glucose-induced platelet microparticles shedding.

BACKGROUND: Platelet microparticles (PMPs) are closely associated with diabetic macrovascular complications. This study aimed to explore the underlying mechanisms of high glucose-induced PMPs generation. METHODS: Washed platelets, obtained from the plasma of healthy male Sprague-Dawley rats, were incubated with high glucose. PMPs were isolated using gradient centrifugation and counted by flow cytometry. Expression and activity of ROCK1 and caspase3 were evaluated by real-time PCR, Western blotting, and activity assay kit. RESULTS: High glucose enhanced PMPs shedding in the presence of collagen. The mRNA and protein levels of ROCK1, but not ROCK2, were increased in platelets incubated with high glucose. Y-27632, an inhibitor of ROCK, blocked the increased PMPs shedding induced by high glucose. Expression and activity of caspase3 were elevated in platelets under the high glucose conditions. Z-DVED-FMK, a caspase3 inhibitor, inhibited ROCK1 activity and decreased the PMPs generation under high glucose. CONCLUSION: High glucose increased PMPs shedding via caspase3-ROCK1 signal pathway.

Aspirin attenuates podocyte injury in diabetic rats through overriding cyclooxygenase-2-mediated dysregulation of LDL receptor pathway.

AIM: This study aimed to investigate the effects of aspirin on podocyte injury and its underlying mechanisms in diabetic nephropathy (DN). METHODS: Eight-week-old male Sprague-Dawley rats were divided into three groups: non-diabetic rats (Control), streptozotocin-induced diabetic rats (DM), and diabetic rats treated with aspirin (DM + Aspirin) for 12 weeks. Intracellular lipid accumulation was evaluated by Oil Red O staining and quantitative free cholesterol assays. Podocyte injury and the levels of COX-2, inflammatory cytokines, and low-density lipoprotein receptor (LDLr) pathway-related proteins were evaluated by electron microscopy, immunohistochemical staining, and Western blotting, respectively. RESULTS: Lipid levels and urinary albumin-creatinine ratios were higher in the DM rats than in the Control rats. Periodic acid-Schiff staining showed glomerular hypertrophy and mild mesangial area widening in the DM rats. Electron microscopy showed that the podocyte foot processes were significantly flattened or absent in the DM rats. The protein expression levels of WT-1 and nephrin in the podocytes of DM rats were reduced. Interestingly, lipid accumulation in the kidneys of DM rats was significantly increased due to increased protein expression levels of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), SREBP-2, cyclooxygenase-2 (COX-2), and inflammatory cytokines. Confocal immunofluorescent staining showed that COX-2 and WT-1 were co-expressed. Furthermore, COX-2 protein expression levels were positively correlated with LDLr protein expression levels. However, when COX-2 expression was inhibited by aspirin, these changes in the DM rats were significantly attenuated. CONCLUSION: Aspirin attenuates podocyte injury in DN, which may be through COX-2-mediated dysregulation of LDLr pathway.