c-Abl contributes to glucose-promoted apoptosis via p53 signaling pathway in podocytes

Ma, Yiqiong; Yang, Qian; Chen, Xinghua; Liang, Wei; Ren, Zhigang; Ding, Guohua

doi:10.1016/j.diabres.2015.12.013

Cited by 9 publications

(10 citation statements)

References 39 publications

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“…As shown in (Fig. 6F-6G), HG ultimately markedly caused podocyte apoptosis, which was consistent with our previous observation 31. Thus, the results demonstrated that HG stimulated- podocyte injury may be attributed to mitochondrial dysfunction, and AMPK alteration might be involved in the regulatory mechanism.…”

Section: Resultssupporting

confidence: 91%

Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation

et al. 2019

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Previous studies have shown that mitochondrial dysfunction plays an important role in high- glucose(HG)-induced podocyte injury and thus contributes to the progression of diabetic nephropathy(DN). The histone deacetylase Sirtuin6 (Sirt6) has been revealed to have an essential role in the regulation of mitochondrial function in skeletal muscle and cardiomyocytes. However, its specific role in mitochondrial homeostasis in podocytes is undetermined. Here, we aimeds to explore the physiological function of Sirt6 in podocyte mitochondria and apoptosis under HG conditions and explore the possible mechanism. Herein, we observed that Sirt6-WT-1 colocalization was suppressed in the glomeruli of patients with DN. In addition, diabetic mice exhibited reduced Sirt6 expression and AMP kinase (AMPK) dephosphorylation accompanied by mitochondrial morphological abnormalities. In vitro, podocytes exposed to HG presented with mitochondrial morphological alterations and podocyte apoptosis accompanied by Sirt6 and p-AMPK downregulation. In addition, HG promoted a decrease in mitochondrial number and an increase in mitochondrial superoxide production as well as a decreased mitochondrial membrane potential. ROS production was also increased in HG-treated podocytes. Conversely, all these mitochondrial defects induced by HG were significantly alleviated by Sirt6 plasmid transfection. Sirt6 overexpression simultaneously alleviated HG-induced podocyte apoptosis and oxidative stress, as well as increased AMPK phosphorylation. Increased levels of H3K9ac and H3K56ac induced by HG were attenuated in podocytes transfected with Sirt6 plasmids. Therefore, these results elucidated that Sirt6 protects mitochondria of podocytes and exerts anti-apoptotic effects via activating AMPK pathway. The present findings provide key insights into the pivotal role of mitochondria regulation by SIRT6 in its protective effects on podocytes.

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Section: Resultssupporting

confidence: 91%

Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation

et al. 2019

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“…As a component of the glomerular filtration barrier, podocyte apoptosis contributes to the pathogenesis of dKd (24,25). Consistent with previous findings (26), the level of podocyte apoptosis was elevated under HG conditions in the present study ( Fig. 5A and B).…”

Section: Discussionsupporting

confidence: 93%

Sestrin‑2 regulates podocyte mitochondrial dysfunction�and apoptosis under high‑glucose conditions via AMPK

Lin

Chen

et al. 2020

Int J Mol Med

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diabetic kidney disease (dKd) is a severe form of microangiopathy among diabetic patients, of which podocyte injury is one of the more predominant features. There is increasing evidence to suggest that mitochondrial dysfunction is associated with podocyte injury, thus contributing to the progression of DKD. Initially identified as a p53 target protein, the endogenous antioxidant protein, sestrin-2 (sesn2), has recently attracted attention due to its potential function in various inflammatory diseases. However, the association between sesn2 and podocytes in dKd remains unclear. In the present study, to elucidate the role of sesn2 in podocyte mitochondrial dysfunction, the effects of sesn2 on the regulation of AMP-activated protein kinase (AMPK) were examined in vitro and in vivo. Abnormal mitochondria were found in rats with streptozotocin-induced diabetes, and hyperglycemia downregulated the expression of sesn2. The upregulation of sesn2 increased the level of AMPK phosphorylation, and thus ameliorated mitochondrial dysfunction under high glucose conditions (HG). On the whole, these results suggest that sesn2 is associated with mitochondrial dysfunction in podocytes under HG conditions. In addition, the decreased expression of sesn2 may be a therapeutic target for dKd.

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“…P53 activation was an early signal for cisplatin-induced renal tubular cell apoptosis (17). Our data are consistent with the findings of other studies that p53 mediated high glucose-induced podocyte apoptosis (27). Aldosterone increased p53 expression in rat mesangial cells.…”

Section: Discussionsupporting

confidence: 91%

p53/Drp1-dependent mitochondrial fission mediates aldosterone-induced podocyte injury and mitochondrial dysfunction

Yuan

Zhang

Jia

et al. 2018

American Journal of Physiology-Renal Physiology

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Mitochondrial dysfunction is increasingly recognized as an important factor in glomerular diseases. Previous study has shown that mitochondrial fission contributed to mitochondrial dysfunction. However, the mechanism of mitochondrial fission on mitochondrial dysfunction in aldosterone-induced podocyte injury remains ambiguous. This study aimed to investigate the pathogenic effect of mitochondrial fission both in vivo and in vitro. In an animal model of aldosterone-induced nephropathy, inhibition of the mitochondrial fission protein dynamin-related protein 1 (Drp1) suppressed aldosterone-induced podocyte injury. In cultured podocytes, aldosterone dose dependently induced Drp1 expression. Knockdown of Drp1 inhibited aldosterone-induced mitochondrial fission, mitochondrial dysfunction, and podocyte apoptosis. Furthermore, aldosterone dose dependently induced p53 expression. Knockdown of p53 inhibited aldosterone-induced Drp1 expression, mitochondrial dysfunction, and podocyte apoptosis. These findings implicated that aldosterone induced mitochondrial dysfunction and podocyte injury mediated by p53/Drp1-dependent mitochondrial fission, which may provide opportunities for therapeutic intervention for podocyte injury.

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c-Abl contributes to glucose-promoted apoptosis via p53 signaling pathway in podocytes

Abstract: c-Abl contributes to high glucose-induced podocyte apoptosis via p53 signaling pathway.

Cited by 9 publications

References 39 publications

Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation

Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation

Sestrin‑2 regulates podocyte mitochondrial dysfunction�and apoptosis under high‑glucose conditions via AMPK

p53/Drp1-dependent mitochondrial fission mediates aldosterone-induced podocyte injury and mitochondrial dysfunction

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