scholarly journals Alleviation by Mahuang Fuzi and Shenzhuo Decoction in High Glucose-Induced Podocyte Injury by Inhibiting the Activation of Wnt/β-Catenin Signaling Pathway, Resulting in Activation of Podocyte Autophagy

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Haoran Dai ◽  
Fei Liu ◽  
Xinping Qiu ◽  
Wenbin Liu ◽  
Zhaocheng Dong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Protective Mechanism ◽  
Podocyte Injury ◽  
Common Endpoint ◽  
Protein Expressions ◽  
Related Proteins ◽  
The Relationship ◽  
Excessive Activation ◽  
Organ Fibrosis

Background. Organ fibrosis is a common endpoint of a variety of diseases. Many studies have shown that the pathogenesis of diabetic kidney disease (DKD) is related to the excessive activation of the Wnt/β-catenin signaling pathway on podocytes, so the treatment of DKD starts from this signaling pathway. At the same time, DKD, as a metabolic disease, has many connections related to podocyte autophagy. Objectives. We experimented the effects of Mahuang Fuzi and Shenzhuo decoction (MFSD) which is the combination of Mahuang Fuzi decoction and Shenzhuo decoction in traditional Chinese medicine compounds used “The Golden Chamber” in high glucose-induced podocytes, determined whether this effect was related to Wnt/β-catenin signaling pathway, and further investigated the relationship between this effect and autophagy. Methods. The mice podocytes were stimulated by using 30 mmol/L of high glucose and serum containing MFSD or Wnt/β-catenin signaling pathway inhibitor DKK1 (100 ng/ml) was used to intervene podocytes before high glucose stimulation. Podocyte injury-related proteins, Wnt/β-catenin signaling pathway-related proteins, and autophagy-related proteins were detected by using western blotting and immunofluorescence analysis. Results. Our results showed that DKK1 and MFSD treatment significantly upregulated the protein expressions of nephrin, podocin, podocalyxin, and podoplanin in high glucose-induced podocytes and downregulated the β-catenin protein expression. Furthermore, the protein expressions of beclin1, LC3B, and P62 were also significantly increased in high glucose-induced podocytes. Conclusion. Our experiments confirmed that the destruction of podocytes in DKD is related to the excessive activation of Wnt/β-catenin signaling pathway and the inhibition of autophagy after activation. MFSD treatment can inhibit the activation of Wnt/β-catenin signaling pathway in podocytes stimulated by high glucose and helpful in reducing the podocyte injury. This protective mechanism can be related to the enhancement of podocyte autophagy by MFSD treatment.

scholarly journals (Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose

2015 ◽  
Vol 309 (3) ◽  
pp. E302-E310 ◽  
Author(s):  
Caixia Li ◽  
Helmy M. Siragy
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Autophagic Flux ◽  
Bafilomycin A1 ◽  
Mtor Signaling Pathway ◽  
Autophagosome Formation ◽  
Podocyte Injury ◽  
Protein Levels

High glucose reduces autophagy and enhances apoptosis of podocytes. Previously, we reported that high glucose induced podocyte injury through upregulation of the (pro)renin receptor (PRR). We hypothesized that increasing PRR reduces autophagy and increases apoptosis of mouse podocytes exposed to high glucose via activation of the PI3K/Akt/mTOR signaling pathway. Mouse podocytes were cultured in normal (5 mmol/l) or high (25 mmol/l) d-glucose for 48 h. High glucose significantly increased mRNA and protein levels of PRR, phosphorylation of PI3K/Akt/mTOR, and p62. In contrast, high glucose decreased activation of UNC-51-like kinase-1 (ULK1) by phosphorylating Ser757 and protein levels of microtubule-associated protein-1 light chain 3B (LC3B)-II and Lamp-2. Bafilomycin A1 increased LC3BII and p62 accumulation in high-glucose-treated cells. High glucose reduced the autophagic flux. Confocal microscopy studies showed significant reduction in the protein level of LC3B in response to high glucose. Cyto-ID autophagy staining showed a significant decrease in autophagosome formation with high glucose. In the absence of PRR, activation of Akt with sc-79 or mTOR with MHY-1485 increased p62 accumulation. Caspase-3/7 activity and apoptosis monitored by TUNEL assay were significantly increased in podocytes treated with high glucose. PRR siRNA significantly reversed the effects of high glucose. Based on these data, we conclude that high glucose decreases autophagy and increases apoptosis in mouse podocytes through the PRR/PI3K/Akt/mTOR signaling pathway.

Silencing of KPNA2 inhibits high glucose-induced podocyte injury via inactivation of mTORC1/p70S6K signaling pathway

2020 ◽  
Vol 521 (4) ◽  
pp. 1017-1023 ◽  
Author(s):  
Xiaobao Fan ◽  
Zhenjiang Li ◽  
Xiaoming Wang ◽  
Jing Wang ◽  
Zhiming Hao
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Podocyte Injury

scholarly journals Islet Transplantation Reverses Podocyte Injury in Diabetic Nephropathy or Induced by High Glucose via Inhibiting RhoA/ROCK/NF-κB Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Chongchu Huang ◽  
Yi Zhou ◽  
Hongjian Huang ◽  
Yushu Zheng ◽  
Lijun Kong ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Islet Transplantation ◽  
High Glucose ◽  
Islet Cells ◽  
Inflammatory Factors ◽  
Efficacy Evaluation ◽  
Podocyte Injury ◽  
Expression Levels

Objective. Abnormal signaling pathways play a crucial role in the mechanisms of podocyte injury in diabetic nephropathy. They also affect the recovery of podocytes after islet transplantation (IT). However, the specific signaling abnormalities that affect the therapeutic effect of IT on podocytes remains unclear. The purpose of this study was to assess whether the RhoA/ROCK/NF-κB signaling pathway is related to podocyte restoration after IT. Methods. A mouse model of diabetic nephropathy was established in vivo using streptozotocin. The mice were then subsequently reared for 4 weeks after islet transplantation to determine the effect of IT. Islet cells, CCG-1423 (RhoA Inhibitor), and fasudil (ROCK inhibitor) were then cocultured with podocytes in vitro to assess their protective effects on podocyte injury induced by high glucose (HG). Protein expression levels of RhoA, ROCK1, synaptopodin, IL-6, and MCP-1 in kidney tissues were then measured using immunohistochemistry and Western blotting techniques. Results. Islet transplantation reduced the expression levels of RhoA/ROCK1 and that of related inflammatory factors such as IL-6 and MCP-1 in the kidney podocytes of diabetic nephropathy. In the same line, islet cells reduced the expression of RhoA, ROCK1, and pp65 in immortalized podocytes under high glucose (35.0 mmol/L glucose) conditions. Conclusions. Islet transplantation can reverse podocyte injury in diabetes nephropathy by inhibiting the RhoA/ROCK1 signaling pathway. Islet cells have a strong protective effect on podocytes treated with high glucose (35.0 mmol/L glucose). Discovery of signaling pathways affecting podocyte recovery is helpful for individualized efficacy evaluation and targeted therapy of islet transplantation patients.

scholarly journals Protective Effects of Thalidomide on High-Glucose-Induced Podocyte Injury through In Vitro Modulation of Macrophage M1/M2 Differentiation

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Hui Liao ◽  
Yuanping Li ◽  
Xilan Zhang ◽  
Xiaoyun Zhao ◽  
Dan Zheng ◽  
...  
Keyword(s):  
High Glucose ◽  
Macrophage Polarization ◽  
Mannose Receptor ◽  
Raw 264.7 Cells ◽  
Protective Effects ◽  
Activated Macrophages ◽  
Podocyte Injury ◽  
Protein Expressions ◽  
Activated Macrophage

Objective. It has been shown that podocyte injury represents an important pathological basis that contributes to proteinuria and eventually leads to kidney failure. High glucose (HG) activates macrophage polarization, further exacerbating HG-induced podocyte injury. Our previous study on diabetic nephropathy rats indicated that thalidomide (Tha) has renoprotective properties. The present study explored the effects of Tha on mRNA and protein expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor- (TNF-) α, mannose receptor (CD206), and arginase- (Arg-) 1 in HG-activated macrophages. iNOS and TNF-α are established as markers of classically activated macrophage (M1). CD206 and Arg-1 are regarded as markers of alternatively activated macrophages (M2). During the experiment, the supernatants of (HG)-treated and (Tha)-treated macrophages, designated as (HG) MS and (Tha) MS, were simultaneously collected and processed. TNF-α and interleukin- (IL-) 1β levels as well as protein expressions of nephrin and podocin in HG, (HG) MS, and (Tha) MS-cultured podocytes were evaluated. The results showed that compared to the 11.1 mM normal glucose (NG), the 33.3 mM HG-cultured RAW 264.7 cells exhibited upregulated iNOS and TNF-α mRNAs and protein expressions, and downregulated CD206 and Arg-1 expressions significantly (p<0.05). Tha 200 μg/ml suppressed iNOS and TNF-α, and promoted CD206 and Arg-1 expressions significantly compared to the HG group (p<0.05). Furthermore, (HG) MS-treated podocytes showed an increase in TNF-α and IL-1β levels and a downregulation in nephrin and podocin expression significantly compared to NG-treated and HG-treated podocytes (p<0.05). The (Tha 200 μg/ml) MS group exhibited a decrease in TNF-α and IL-1β level, and an upregulation in nephrin and podocin expressions significantly compared to the (HG) MS group (p<0.05). Our research confirmed that HG-activated macrophage differentiation aggravates HG-induced podocyte injury in vitro and the protective effects of Tha might be related to its actions on TNF-α and IL-1β levels via its modulation on M1/M2 differentiation.

scholarly journals Dexamethasone reduces podocyte injury through the PTEN-PI3K/Akt signaling pathway

2021 ◽  
Author(s):  
Qi rRen ◽  
Shengyou Yu ◽  
Huasong Zeng ◽  
Huimin Xia
Keyword(s):  
Signaling Pathway ◽  
Akt Signaling ◽  
Final Concentration ◽  
Pten Gene ◽  
Control Group ◽  
Protective Mechanism ◽  
Akt Signaling Pathway ◽  
Podocyte Injury ◽  
Pten Protein ◽  
Podocyte Damage

Abstract Objective: To study the role of Akt and its downstream molecules in the PTEN-PI3K/Akt signaling pathway, namely,GSK3β and Bad, in the Dexamethasone(DEX)-mediated regulation of PAN-induced glomerular podocyte injury and to elucidate the molecular mechanism of podocyte injury regulation. Methods: Glomerular podocytes (MPC5) were cultured in vitro and divided into four groups: the control group, PTEN silencing group (siPTEN group), puromycin group (PAN group), and puromycin group + DEX group (PAN+ DEX group). The cells in each group were treated for 8h, 24h, and 48h, and then, the experiment was carried out. The cells in the control group were cultured in RPMI 1640 with 0.02% DMSO, the cells in the siPTEN group were used to construct a silencing kit, the podocytes in the PAN group were treated with puromycin (final concentration of 50μg/ml), and the podocytes in the DEX+PAN group were pretreated with 0.1μmol/L DEX followed by PAN (final concentration of 50μg/ml). An inverted phase contrast microscope was used to observe the morphological changes in the podocytes and the changes in the cell body area in each group, laser confocal microscopy was used to detect the expression and distribution of the PTEN protein, and flow cytometry was used to detect and analyze the apoptosis rate and mitochondrial membrane potential of each group of podocytes. Western blot was used to detect the expression of the PTEN, P-Akt, Akt, P-GSK3β and GSK3β proteins in each group of podocytes, and transmission electron microscopy was used to observe the changes in the morphology and structure of each group of podocytes. Results: After PAN was used to injure the podocytes, the expression of the PTEN protein decreased, the rate of apoptosis increased, and the flux of autophagy was inhibited. DEX treatment reversed the changes described above.After PAN was used to injure the podocytes, the expression of p-Ak and p-GSK3β decreased, and DEX reversed these effects on the expression of p-Akt and p-GSK3β in the podocytes. Compared with the control group, in the PAN group, the mitochondria gradually swelled and rounded, mitochondrial cristae arrangement became disordered, mitochondrial autophagy was inhibited; DEX reversed the changes described above after the PTEN gene was silenced. Conclusion: This study confirmed that PAN can inhibit podocyte autophagy and induce podocyte damage. DEX can reduce the PAN-induced suppression of podocyte autophagy, enhance podocyte autophagy, and ameliorate podocyte damage. The protective mechanism may be through the upregulation of PTEN expression, which is achieved by inhibiting the activation of the PI3K/Akt signaling pathway.

scholarly journals Yi-Qi-Ping-Chuan-Fang Reduces TSLP Elevation Caused by LPS + Poly(I:C) via Inhibiting TLR4/MYD88/NF-κB Signaling Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Minye Qu ◽  
Xiang Tao ◽  
Jian Ma
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Primary Response ◽  
Poly I:C ◽  
Myeloid Differentiation ◽  
Bronchial Epithelial ◽  
Chinese Medicine Formula ◽  
Primary Response Gene ◽  
Protein Expressions ◽  
Related Proteins

Objective. To explore the correlation between Thymic Stromal Lymphopoietin (TSLP) and the Nuclear Factor- (NF-) κB signaling pathways in bronchial epithelial cells and to clarify whether the traditional Chinese medicine formula Yi-Qi-Ping-Chuan-Fang (YQPC) reduces inflammation by inhibiting TSLP/NF-κB signaling pathways. Methods. Cells were stimulated with LPS + Poly(I:C) and treated with YQPC. The expressions of TSLP and NF-κB signaling pathways related proteins P65, IκK, IκBa, P-P65, P-IκK, P-IκBa were detected. The effects of NF-κB upstream molecules, Toll-like receptors 3 and 4, myeloid differentiation primary response gene 88 (Myd88), TIR-domain-containing adapter-inducing interferon-β (TRIF), and downstream inflammatory cytokines, TNF-α, IL-1β, IL-6, and IL-8, were assessed. Results. The mRNA and protein expressions of TSLP were significantly increased after LPS + Poly(I:C) stimulation, the total protein IκBa and IκK decreased (P < 0.05), and the phosphorylated protein P-P65, P-IκK, and P-IκBα increased. After YQPC treatment, the expression of TSLP, P-P65, P-IκBa, and P-IκK was significantly inhibited (P < 0.05). The activation of TLR4 and MyD88 decreased, and release of IL-1β, IL-6, IL-8, and TNF-α reduced (P < 0.05). Conclusion. In summary, the expression of TSLP is activated by the NF-κB signaling pathway. YQPC alleviated inflammation by inhibiting TSLP through regulating the NF-κB activation and translocation.

scholarly journals Hydrogen-Rich Saline Inhibits Lipopolysaccharide-Induced Acute Lung Injury and Endothelial Dysfunction by Regulating Autophagy through mTOR/TFEB Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Zhiling Fu ◽  
Ze Zhang ◽  
Xiuying Wu ◽  
Jin Zhang
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antioxidative Stress ◽  
Related Proteins ◽  
The Relationship ◽  
Apoptosis Proteins

Background. Hydrogen-rich saline (HRS) has strong anti-inflammatory, antioxidative stress, and antiapoptotic properties. The study focused on the protection of HRS on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rat models and the relationship with autophagic regulation and mTOR/TFEB signaling pathway. Material and Methods. The LPS-induced ALI rats’ model was established. Pathohistological change in lung tissue was detected by hematoxylin-eosin staining. The inflammatory cytokines were examined by enzyme-linked immunosorbent assay (ELISA). The key apoptosis proteins and autophagy-relevant proteins were analyzed by western blotting. In vitro, HPMEC models of ALI were treated with LPS. The inflammatory cytokines were detected. Apoptosis rate was determined by flow cytometry. The autophagy and mTOR/TFEB signaling pathway-related proteins were detected by western blot and immunohistochemical staining. Results. HRS attenuated LPS-induced ALI and apoptosis both in vivo and in vitro. HRS attenuated inflammatory response, inhibited apoptosis, induced and activated autophagy in LPS-induced ALI model, and downregulated mTOR/TFEB signaling pathway. The protection of HRS can be blocked by autophagy inhibitor. Moreover, mTOR activator reversed HRS protection and mTOR inhibitor enhanced HRS protection in LPS-induced model and HRS activated autophagy via mTOR/TFEB signaling pathway. Conclusion. The results confirmed the protection of HRS in LPS-induced ALI by regulating apoptosis through inhibiting the mTOR/TFEB signaling pathway.

scholarly journals D-Limonene Is a Potential Monoterpene to Inhibit PI3K/Akt/IKK-α/NF-κB p65 Signaling Pathway in Coronavirus Disease 2019 Pulmonary Fibrosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Fan Yang ◽  
Ru Chen ◽  
Wan-yang Li ◽  
Hao-yue Zhu ◽  
Xiao-xuan Chen ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Rat Lung ◽  
Akt Signaling Pathway ◽  
Pharmacological Targets ◽  
Pathway Expression ◽  
Therapeutic Value ◽  
Related Proteins ◽  
The Relationship

At the time of the prevalence of coronavirus disease 2019 (COVID-19), pulmonary fibrosis (PF) related to COVID-19 has become the main sequela. However, the mechanism of PF related to COVID (COVID-PF) is unknown. This study aimed to explore the key targets in the development of COVID-PF and the mechanism of d-limonene in the COVID-PF treatment. The differentially expressed genes of COVID-PF were downloaded from the GeneCards database, and their pathways were analyzed. d-Limonene was molecularly docked with related proteins to screen its pharmacological targets, and a rat lung fibrosis model was established to verify d-limonene's effect on COVID-PF-related targets. The results showed that the imbalance between collagen breakdown and metabolism, inflammatory response, and angiogenesis are the core processes of COVID-PF; and PI3K/AKT signaling pathways are the key targets of the treatment of COVID-PF. The ability of d-limonene to protect against PF induced by bleomycin in rats was reported. The mechanism is related to the binding of PI3K and NF-κB p65, and the inhibition of PI3K/Akt/IKK-α/NF-κB p65 signaling pathway expression and phosphorylation. These results confirmed the relationship between the PI3K–Akt signaling pathway and COVID-PF, showing that d-limonene has a potential therapeutic value for COVID-PF.

scholarly journals Lanthanum Chloride Causes Neurotoxicity in Rats by Upregulating miR-124 Expression and Targeting PIK3CA to Regulate the PI3K/Akt Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Linlin Zheng ◽  
Jinhui Zhang ◽  
Shengjin Yu ◽  
Zhe Ding ◽  
Heling Song ◽  
...  
Keyword(s):  
Nervous System ◽  
Signaling Pathway ◽  
Learning And Memory ◽  
Intellectual Development ◽  
Akt Signaling ◽  
Luciferase Assay ◽  
Akt Signaling Pathway ◽  
Related Proteins ◽  
The Relationship

Background. Lanthanum (La) exposure can cause central nervous system (CNS) damage and dysfunction in children, seriously affecting intellectual development. miR-124 plays an important role in the development of the nervous system. We exposed rats to a La environment then observed the rats’ learning and memory damage and neurotoxicity and the relationship with miR-124. Methods. Rats were exposed to LaCl3 via drinking water. The rats’ offspring were exposed to LaCl3 from their mother before weaning, then from La water for 28 days. A Morris water maze was used to observe spatial memory capabilities. H&E staining and TUNEL assays were used to observe pathological changes and apoptosis in the hippocampus. miR-124 was detected by RT-qPCR, and its targeting was confirmed by luciferase assay. The HT22 cell line was cultured with LaCl3 and treated with miR-124 mimics or inhibitors; then, expression of PI3K/Akt-related proteins was detected by western blot. Results. La exposure can lead to impaired learning and memory ability in offspring. Offspring with La accumulations in the hippocampus showed severe damage, disordered cells, and increased neurocyte apoptosis. In vitro, the postsynaptic density protein 95 was downregulated under La exposure and apoptosis increased. This effect of La can be attenuated by miR-124 inhibitors and enhanced by miR-124 mimics. LaCl3 exposure increased miR-124 expression and targeting on PIK3CA, downregulating PI3K, p-Akt, and p-NF-κB p65. Conclusion. La causes neurotoxicity by upregulating miR-124 expression and targeting PIK3CA through the PI3K/Akt signaling pathway.

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