Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes

Jin, Yingli; Liu, Shuping; Ma, Qingshan; Xiao, Dong; Chen, Li

doi:10.1016/j.ejphar.2016.11.037

Cited by 98 publications

(64 citation statements)

References 34 publications

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“…As reported previously [8-11, 24, 25], mouse podocytes are damaged under HG culture conditions. We provide evidence that ER stress and mTOR signaling is involved in HG-induced podocyte injury.…”

Section: Discussionmentioning

confidence: 50%

“…1B). Although other groups also reported HG-induced podocyte apoptosis [8-11, 24], the underlying mechanisms are still elusive.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that high glucose can induce podocyte injury [8-11, 24-26]. Accordingly, in comparison with normal glucose (NG) and osmotic mannitol (MN) control, we found that the percentage of apoptotic cells significantly increased at 12 (HG 5.93 ± 0.603 vs NG 2.17 ± 1.00 and MN 2.47 ± 0.901, p < 0.05), 24 (HG 11.17 ± 1.061 vs NG 2.10 ± 0.562 and MN 2.43 ± 0.742, p < 0.001) and 48 h (HG 16.27 ± 0.874 vs NG 2.63 ± 0.351 and MN 2.97 ± 0.351, p <0.001) in high glucose (HG)-treated podocytes (Fig.…”

Section: Resultsmentioning

confidence: 99%

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High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

Lei

Zhao

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The mechanisms by which high glucose (HG) results in podocyte damage remains unclear. We investigated the potential role of endoplasmic reticulum (ER) stress and mTOR signaling in HG injured podocyte. Methods: In cultured mouse podocytes, cellular apoptosis was assessed using FITC-Annexin V and propidium iodide staining followed by flow cytometry analysis. Apoptosis-related proteins as well as the ER stress and the mTOR signals were evaluated using immunoblot assay. Results: Compared to normal glucose (NG) and osmotic mannitol (MN) control, the percentage of apoptotic cells was increased significantly in HG-treated podocytes. The levels of CHOP, Grp78, phospho-PERKThr982, and caspase-12 were increased significantly following HG treatment. The downstream effects of ER stress were obtained in HG-treated podocytes, showing upregulation of Bax, Bak and cytochrome c, and downregulation of Bcl-2. HG-induced increase of cytochrome c, Bax and active caspase-3 was prevented by both ER inhibitor sodium 4-phenylbultyrate (PBA) and CHOP siRNA (siCHOP). PBA and CHOP knockdown remarkably decreased HG-induced apoptosis. In addition, the levels of phospho-mTORSer2448 and phospho- p70S6kThr389 as well as phospho-AMPKα (a sensor of energy consumption) were increased significantly in HG-treated cells. Moreover, the Erk inhibitor U0126 prevented HG-induced mTOR activation. Increased phospho-AMPKα, CHOP and Grp78 as well as cellular apoptosis were prevented by mTOR inhibitor rapamycin in HG-treated podocytes. Conclusion: Our data demonstrate that the activated mTOR by Erk1/2 results in energy consumption, which in turn leads to ER stress signaling and thus induces apoptosis in HG-treated podocytes.

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Section: Discussionmentioning

confidence: 50%

“…1B). Although other groups also reported HG-induced podocyte apoptosis [8-11, 24], the underlying mechanisms are still elusive.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

Lei

Zhao

Zhang

et al. 2018

Cell Physiol Biochem

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“…In the condition of ATP deficiency, the downstream TSC1/2 is activated by AMPK, then inhibits Rheb, and finally enhances autophagy by suppressing mTOR activation (Figure 1). Recently, Jin et al suggested that berberine alleviated high glucose-induced apoptosis of podocytes in mouse via increasing the activity of AMPK [44]. They showed that the expression of p-AMPK in a high-glucose (HG) group was lower and the expression of p-mTOR was higher in the HG group compared with the control group, while these results were conversed by berberine administration.…”

Section: Podocyte Autophagy In Diabetic Nephropathymentioning

confidence: 99%

Podocyte Autophagy: A Potential Therapeutic Target to Prevent the Progression of Diabetic Nephropathy

Liu

Shi

et al. 2017

Journal of Diabetes Research

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Diabetic nephropathy (DN), a leading cause of end-stage renal disease (ESRD), becomes a worldwide problem. Ultrastructural changes of the glomerular filtration barrier, especially the pathological changes of podocytes, lead to proteinuria in patients with diabetes. Podocytes are major components of glomerular filtration barrier, lining outside of the glomerular basement membrane (GBM) to maintain the permeability of the GBM. Autophagy is a high conserved cellular process in lysosomes including impaired protein, cell organelles, and other contents in the cytoplasm. Recent studies suggest that activation of autophagy in podocytes may be a potential therapy to prevent the progression of DN. Here, we review the mechanisms of autophagy in podocytes and discuss the current studies about alleviating proteinuria via activating podocyte autophagy.

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“…Clinical data demonstrate that podocyte integrity is impaired, and the decreased podocyte number is confirmed in individuals with type 1 (T1DM) and 2 diabetes mellitus (T2DM) (4,5). In cultured podocytes, high glucose induces apoptosis, epithelial-mesenchymal transition (EMT), mitochondrial fission and autophagy through different signaling pathways (6)(7)(8)(9). However, the underlying molecular mechanisms of high glucose-induced MPC5 podocytes dysfunction remain to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of miR‑130a‑3p/301a‑3p attenuates high glucose‑induced MPC5 podocyte dysfunction through suppression of TNF‑α signaling

Jiang

Wang²,

Liu

et al. 2017

Exp Ther Med

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Abstract. Tumor necrosis factor (TNF)-α has been reported to be important in glomerulonephritis, which is closely associated with podocyte dysfunction and apoptosis. However, the precise mechanisms by which TNF-α expression are regulated remain unclear. The purpose of the present study was to investigate the role of microRNA (miR)-130a-3p/301a-3p in the post-transcriptional control of TNF-α expression and high glucose (HG)-induced podocyte dysfunction. Mice MPC5 podocytes were incubated with HG and transfected with miR-130a-3p/301a-3p mimics or inhibitors, reactive oxygen species (ROS) levels were measured by flow cytometry assay, and the mRNA and protein levels were assayed by using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The targeted genes were predicted by a bioinformatics algorithm and verified using a dual luciferase reporter assay. It was observed that miR-130a-3p/301a-3p was a novel regulator of TNF-α in mouse podocytes. miR-130a-3p/301a-3p mimics inhibited TNF-α 3'-untranslated region luciferase reporter activity, in addition to endogenous TNF-α protein expression. Furthermore, forced expression of miR-130a-3p or miR-301a-3p resulted in the downregulation of ROS and malondialdehyde (MDA) and the upregulation of superoxide dismutase (SOD) 1 in the presence of HG. Inhibition of TNF-α level prevented a remarkable reduc tion in SOD activity and a marked increase in ROS and MDA levels in HG-treated podocytes. Furthermore, TNF-α loss-of-function significantly reversed HG-induced podocyte apoptosis. These data demonstrated a novel up-stream role for miR-130a-3p/301a-3p in TNF-α-mediated podocyte dysfunction and apoptosis in the presence of HG. IntroductionGlomerular podocytes are highly differentiated cells that play a key role in maintaining the integrity of the glomerular filtration barrier (1). In glomerular diseases, podocyte damage leads to increased glomerular barrier pore size, allowing the passage of proteins or other mediators to the tubular lumen, which results in proteinuria and progressive loss of kidney function (2). Accumulating evidence indicates that hyperglycemia contributes to podocyte lesions (3). Clinical data demonstrate that podocyte integrity is impaired, and the decreased podocyte number is confirmed in individuals with type 1 (T1DM) and 2 diabetes mellitus (T2DM) (4,5). In cultured podocytes, high glucose induces apoptosis, epithelial-mesenchymal transition (EMT), mitochondrial fission and autophagy through different signaling pathways (6-9). However, the underlying molecular mechanisms of high glucose-induced MPC5 podocytes dysfunction remain to be fully elucidated.MicroRNAs (miRs) are endogenous, noncoding, short, single-stranded RNAs (18-25 nucleotides) that are evolutionarily highly conserved, believed to regulate the translation of target messenger RNAs (mRNAs) by binding to its 3'-untranslated regions (3'-UTRs) and verified to play a role in controlling a variety of biological processes (10). Recently, several studies have h...

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Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes

Cited by 98 publications

References 34 publications

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

Podocyte Autophagy: A Potential Therapeutic Target to Prevent the Progression of Diabetic Nephropathy

Overexpression of miR‑130a‑3p/301a‑3p attenuates high glucose‑induced MPC5 podocyte dysfunction through suppression of TNF‑α signaling

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