EDA2R mediates podocyte injury in high glucose milieu

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.

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KCNQ1OT1 inhibition alleviates high glucose-induced podocyte injury by adsorbing miR-23b-3p and regulating Sema3A

Clinical and Experimental Nephrology ◽

10.1007/s10157-021-02173-x ◽

2022 ◽

Author(s):

Bingru Fei ◽

Hui Zhou ◽

Zengjiao He ◽

Suyu Wang

Keyword(s):

High Glucose ◽

Podocyte Injury

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Increased long noncoding RNA maternally expressed gene 3 contributes to podocyte injury induced by high glucose through regulation of mitochondrial fission

Cell Death and Disease ◽

10.1038/s41419-020-03022-7 ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

Qiongxia Deng ◽

Ruowei Wen ◽

Sirui Liu ◽

Xiaoqiu Chen ◽

Shicong Song ◽

...

Keyword(s):

High Glucose ◽

Noncoding Rna ◽

Diabetic Kidney Disease ◽

Mitochondrial Fission ◽

Diabetic Mice ◽

Podocyte Injury ◽

Mitochondrial Translocation ◽

Maternally Expressed Gene 3

Abstract Excessive mitochondrial fission plays a key role in podocyte injury in diabetic kidney disease (DKD), and long noncoding RNAs (lncRNAs) are important in the development and progression of DKD. However, lncRNA regulation of mitochondrial fission in podocytes is poorly understood. Here, we studied lncRNA maternally expressed gene 3 (Meg3) in mitochondrial fission in vivo and in vitro using human podocytes and Meg3 podocyte-specific knockdown mice. Expression of lncRNA Meg3 in STZ-induced diabetic mice was higher, and correlated with the number of podocytes. Excessive mitochondrial fission of podocytes and renal histopathological and physiological parameters were improved in podocyte-specific Meg3 knockdown diabetic mice. Elongated mitochondria with attenuated podocyte damage, as well as mitochondrial translocation of dynamin-related protein 1 (Drp1), were decreased in Meg3 knockout podocytes. By contrast, increased fragmented mitochondria, podocyte injury, and Drp1 expression and phosphorylation were observed in lncRNA Meg3-overexpressing podocytes. Treatment with Mdivi1 significantly blunted more fragmented mitochondria and reduced podocyte injury in lncRNA Meg3-overexpressing podocytes. Finally, fragmented mitochondria and Drp1 mitochondrial translocation induced by high glucose were reduced following treatment with Mdivi1. Our data show that expression of Meg3 in podocytes in both human cells and diabetic mice was higher, which regulates mitochondrial fission and contributes to podocyte injury through increased Drp1 and its translocation to mitochondria.

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Store‐operated calcium entry mediated high glucose‐induced podocyte injury and mitochondrial impairment

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.05102 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Yu Tao ◽

Sarika Chaudhari ◽

Parisa Shotorbani ◽

Rong Ma

Keyword(s):

High Glucose ◽

Calcium Entry ◽

Podocyte Injury ◽

Mitochondrial Impairment ◽

Store Operated Calcium Entry

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Sulfiredoxin-1 alleviates high glucose-induced podocyte injury though promoting Nrf2/ARE signaling via inactivation of GSK-3β

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2019.06.157 ◽

2019 ◽

Vol 516 (4) ◽

pp. 1137-1144 ◽

Cited By ~ 3

Author(s):

Yan Shen ◽

Shengnan Chen ◽

Yan Zhao

Keyword(s):

High Glucose ◽

Podocyte Injury ◽

Gsk 3Β

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Bone morphogenetic protein-7 delays podocyte injury due to high glucose

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfm503 ◽

2007 ◽

Vol 22 (12) ◽

pp. 3442-3450 ◽

Cited By ~ 44

Author(s):

L. De Petris ◽

K. A. Hruska ◽

S. Chiechio ◽

H. Liapis

Keyword(s):

Bone Morphogenetic Protein ◽

High Glucose ◽

Podocyte Injury ◽

Bone Morphogenetic Protein 7 ◽

Morphogenetic Protein

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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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/7809427 ◽

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.

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