Paecilomyces cicadae-fermented Radix astragali activates podocyte autophagy by attenuating PI3K/AKT/mTOR pathways to protect against diabetic nephropathy in mice

Yang, Fang; Qu, Qingsong; Zhao, Chongyan; Liu, Xing; Yang, Pengshuo; Li, Zhixun; Han, Lu; Shi, Xinyuan

doi:10.1016/j.biopha.2020.110479

Cited by 56 publications

(35 citation statements)

References 33 publications

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“…Studies have shown that the PI3K/Akt pathway is overactivated in DN. Inhibition of the PI3K/Akt pathway can promote autophagy and reduce podocyte injury (Yang et al, 2020). This is consistent with the results observed in this study.…”

Section: Discussionsupporting

confidence: 93%

“…Unfortunately, however, a large number of studies have shown that the autophagic activity of podocytes is inhibited in DN (Kume et al, 2014;Tagawa et al, 2016). Autophagy is mainly regulated by the mTOR pathway, and current studies have shown that selective inhibition of mTOR pathway activity can promote autophagy and improve podocyte damage and renal function (Codogno and Meijer, 2005;Yang et al, 2020). The activity of the mTOR pathway is mainly regulated by the PI3K/Akt and AMPK pathways (Yang and Klionsky, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Yiqi Jiedu Huayu Decoction Alleviates Renal Injury in Rats With Diabetic Nephropathy by Promoting Autophagy

Chen

Zhang

et al. 2021

Front. Pharmacol.

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Diabetic nephropathy (DN), a common microvascular complication of diabetes, is one of the main causes of end-stage renal failure (ESRD) and imposes a heavy medical burden on the world. Yiqi Jiedu Huayu decoction (YJHD) is a traditional Chinese medicine formula, which has been widely used in the treatment of DN and has achieved stable and reliable therapeutic effects. However, the mechanism of YJHD in the treatment of DN remains unclear. This study aimed to investigate the mechanism of YJHD in the treatment of DN. Sprague-Dawley rats were randomly divided into a normal control group, a diabetic group, an irbesartan group, and three groups receiving different doses of YJHD. Animal models were constructed using streptozotocin and then treated with YJHD for 12 consecutive weeks. Blood and urine samples were collected during this period, and metabolic and renal function was assessed. Pathological kidney injury was evaluated according to the kidney appearance, hematoxylin-eosin staining, Masson staining, periodic-acid Schiff staining, periodic-acid Schiff methenamine staining, and transmission electron microscopy. The expression levels of proteins and genes were detected by immunohistochemistry, western blotting, and real-time qPCR. Our results indicate that YJHD can effectively improve renal function and alleviate renal pathological injury, including mesangial matrix hyperplasia, basement membrane thickening, and fibrosis. In addition, YJHD exhibited podocyte protection by alleviating podocyte depletion and morphological damage, which may be key in improving renal function and reducing renal fibrosis. Further study revealed that YJHD upregulated the expression of the autophagy-related proteins LC3II and Beclin-1 while downregulating p62 expression, suggesting that YJHD can promote autophagy. In addition, we evaluated the activity of the mTOR pathway, the major signaling pathway regulating the level of autophagy, and the upstream PI3K/Akt and AMPK pathways. YJHD activated the AMPK pathway while inhibiting the PI3K/Akt and mTOR pathways, which may be crucial to its promotion of autophagy. In conclusion, our study shows that YJHD further inhibits the mTOR pathway and promotes autophagy by regulating the activity of the PI3K/Akt and AMPK pathways, thereby improving podocyte injury, protecting renal function, and reducing renal fibrosis. This study provides support for the application of and further research into YJHD.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Yiqi Jiedu Huayu Decoction Alleviates Renal Injury in Rats With Diabetic Nephropathy by Promoting Autophagy

Chen

Zhang

et al. 2021

Front. Pharmacol.

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“…These cellular functions include cell growth, proliferation, differentiation, motility, and survival (Jafari et al, 2019). Regulation of the PI3K/Akt signaling pathway has been increasingly implicated in protecting podocytes in DKD (Song et al, 2014;Wang et al, 2014;Yang et al, 2020). In addition, phosphate and tension homology (PTEN) is a form of 3,4,5-triphosphate inositol lipase that negatively regulates the PI3K signaling pathway (Maidarti et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Total Flavones of Abelmoschus manihot Ameliorates Podocyte Pyroptosis and Injury in High Glucose Conditions by Targeting METTL3-Dependent m6A Modification-Mediated NLRP3-Inflammasome Activation and PTEN/PI3K/Akt Signaling

Liu

et al. 2021

Front. Pharmacol.

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Background: The total flavones of Abelmoschus manihot (TFA), a compound that is extracted from Abelmoschus manihot, has been widely used in China to reduce podocyte injury in diabetic kidney disease (DKD). However, the mechanisms underlying the therapeutic action of this compound have yet to be elucidated. Podocyte pyroptosis is characterized by activation of the NLRP3 inflammasome and plays an important role in inflammation-mediated diabetic kidneys. Regulation of the PTEN/PI3K/Akt pathway is an effective strategy for improving podocyte damage in DKD. Previous research has also shown that N6-methyladenosine (m6A) modification is involved in DKD and that m6A-modified PTEN regulates the PI3K/Akt pathway. In this study, we investigated whether TFA alleviates podocyte pyroptosis and injury by targeting m6A modification-mediated NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling.Methods: We used MPC-5 cells under high glucose (HG) conditions to investigate the key molecules that are involved in podocyte pyroptosis and injury, including activation of the NLRP3 inflammasome and the PTEN/PI3K/Akt pathway. We detected alterations in the levels of three methyltransferases that are involved in m6A modification. We also investigated changes in the levels of these key molecules in podocytes with the overexpression or knockdown of methyltransferase-like (METTL)3.Results: Analysis showed that TFA and MCC950 protected podocytes against HG-induced pyroptosis and injury by reducing the protein expression levels of gasdermin D, interleukin-1β, and interleukin-18, and by increasing the protein expression levels of nephrin, ZO-1, WT1 and podocalyxin. TFA and 740Y-P inhibited activation of the NLRP3 inflammasome via the PI3K/Akt pathway by inhibiting the protein levels of NIMA-related kinase7, NLRP3, ASC, and caspase-1, and by increasing the protein expression levels of p-PI3K and p-Akt. TFA improved pyroptosis and injury in HG-stimulated podocytes by regulating METTL3-dependent m6A modification.Conclusion: Collectively, our data indicated that TFA could ameliorate pyroptosis and injury in podocytes under HG conditions by adjusting METTL3-dependent m6A modification and regulating NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling. This study provides a better understanding of how TFA can protect podocytes in DKD.

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“…PI3K/Akt/mTOR signaling pathway is related to many cellular processes, including the regulation of apoptosis, inflammation, autophagy. 23,24 Previous studies illustrated that PI3K/Akt/mTOR signaling mediated high glucose induced podocytes injury via restraining podocytes autophagy, [34][35][36] indicating targeting this signaling is a promising way to ameliorate DN progression. In addition, studies have reported that EGF can regulate PI3K/Akt/mTOR signaling pathways in various cancer.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Protects Against High Glucose-Induced Podocyte Injury Possibly via Modulation of Autophagy and PI3K/AKT/mTOR Signaling Pathway Through DNA Methylation

Sun¹,

Deng

et al. 2021

DMSO

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Aim: Diabetic nephropathy (DN) is a serious health problem worldwide. Epidermal growth factor (EGF) has suggested as a potential biomarker for the progression of chronic kidney disease. In this study, we examined the effects of EGF on the high glucose (HG)-induced podocyte injury and explored the underlying molecular mechanisms. Methods: The cell proliferation, toxicity, and cell apoptosis of podocytes were determined by CCK-8 assay, lactate dehydrogenase release assay, and flow cytometry, respectively, and protein levels in the podocytes were determined by Western blot assay. Mechanistically, DNA methylation analysis, bioinformatic analysis, methylation-specific PCR and quantitative real-time PCR were used to analyze functional pathways in differentially methylated genes and the expression of the key methylated genes in the podocytes after different interventions.Results: EGF treatment significantly increased the protein expression level of LC3 and decreased the protein level of P62 in HG-stimulated podocytes, which was attenuated by autophagy inhibitor, 3-methyladenine. EGF increased the cell proliferation and the protein expression levels of nephrin and synaptopodin, but reduced cell toxicity and cell apoptosis and protein expression level of cleaved caspase-3, which was partially antagonized by 3-methyladenine. DNA methylation expression profiles revealed the differential hypermethylation sites and hypomethylation sites among podocytes treated with normal glucose, HG and HG+EGF. GO enrichment analysis showed that DNA methylation was significantly enriched in negative regulation of phosphorylation, cellcell junction and GTPase binding. KEGG pathway analysis showed that these genes were mainly enriched in PI3K-Akt, Hippo and autophagy pathways. Further validation studies revealed that six hub genes (ITGB1, GRB2, FN1, ITGB3, FZD10 and FGFR1) may be associated with the protective effects of EGF on the HG-induced podocyte injury. Conclusion:In summary, our results demonstrated that EGF exerted protective effects on HG-induced podocytes injury via enhancing cell proliferation and inhibiting cell apoptosis. Further mechanistic studies implied that EGF-mediated protective effects in HG-stimulated podocytes may be associated with modulation of autophagy and PI3K/AKT/mTOR signaling pathway.

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Paecilomyces cicadae-fermented Radix astragali activates podocyte autophagy by attenuating PI3K/AKT/mTOR pathways to protect against diabetic nephropathy in mice

Cited by 56 publications

References 33 publications

Yiqi Jiedu Huayu Decoction Alleviates Renal Injury in Rats With Diabetic Nephropathy by Promoting Autophagy

Yiqi Jiedu Huayu Decoction Alleviates Renal Injury in Rats With Diabetic Nephropathy by Promoting Autophagy

Total Flavones of Abelmoschus manihot Ameliorates Podocyte Pyroptosis and Injury in High Glucose Conditions by Targeting METTL3-Dependent m6A Modification-Mediated NLRP3-Inflammasome Activation and PTEN/PI3K/Akt Signaling

Epidermal Growth Factor Protects Against High Glucose-Induced Podocyte Injury Possibly via Modulation of Autophagy and PI3K/AKT/mTOR Signaling Pathway Through DNA Methylation

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