NR4A1 contributes to high-fat associated endothelial dysfunction by promoting CaMKII-Parkin-mitophagy pathways

Li, Pei; Bai, Yuzhi; Zhao, Xia; Tian, Tian; Tang, Liying; Ru, Jing; An, Yun Suk; Wang, Jing

doi:10.1007/s12192-018-0886-1

Cited by 42 publications

(39 citation statements)

References 64 publications

(64 reference statements)

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“…Consistently with our findings, previous studies have reported that DUSP1 downregulation was noted in fatty liver disease and cardiac ischemia reperfusion injury (Li et al, ; Pickard, Burke, Davidson, & Yellon, ; Zhou et al, ) via modifying mitochondrial function, and that DUSP1 overexpression or pharmacological activation of DUSP1 retards or prevents the progression of nonalcoholic fatty liver and cardiac ischemia reperfusion injury. Collectively, these observations have demonstrated the sufficiency of DUSP1 to modulate mitochondrial metabolic diseases, which may highlight a new entry point for treating chronic metabolic disorder by targeting DUSP1.…”

Section: Discussionsupporting

confidence: 93%

DUSP1 recuses diabetic nephropathy via repressing JNK‐Mff‐mitochondrial fission pathways

Sheng

Dai

et al. 2018

Journal Cellular Physiology

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Excessive mitochondrial fission has been identified as the pathogenesis of diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation in the setting of DN remains unknown. In the current study, we found that dual-specificity protein phosphatase-1 (DUSP1) was actually downregulated by chronic hyperglycemia stimulus. Lower DUSP1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, defective DUSP1 expression activated JNK pathway, and the latter selectively opened mitochondrial fission by modulating mitochondrial fission factor (Mff) phosphorylation. Excessive Mff-related mitochondrial fission evoked mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria-dependent cellular apoptosis in the setting of diabetes. However, overexpression of DUSP1 interrupted Mff-related mitochondrial fission, reducing hyperglycemia-mediated mitochondrial damage and thus improving renal function. Overall, we have shown that DUSP1 functions as a novel malefactor in diabetic renal damage that mediates via modifying Mff-related mitochondrial fission. Thus, finding strategies to regulate the balance of the DUSP1-JNK-Mff signaling pathway and mitochondrial homeostasis may be a therapeutic target for treating diabetic nephropathy in clinical practice.

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Section: Discussionsupporting

confidence: 93%

DUSP1 recuses diabetic nephropathy via repressing JNK‐Mff‐mitochondrial fission pathways

Sheng

Dai

et al. 2018

Journal Cellular Physiology

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“…Interestingly, the JNK pathway has been confirmed to be the upstream signal for mitochondrial fragmentation [18]. Other studies also suggest that CaMKII phosphorylation and Fis1 upregulation also participate into the regulation of mitochondrial fragmentation [44,45]. Based on these findings, we examined whether MKP1 controlled mitochondrial fragmentation via the JNK-CaMKII-Fis1 pathway.…”

Section: Mkp1 Controls Mitochondrial Fragmentation Via Inhibiting Thementioning

confidence: 88%

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Zhang¹,

Feng²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hyperglycaemia stress-induced renal injury is closely associated with mitochondrial dysfunction through poorly understood mechanisms. The aim of our study is to explore the upstream trigger and the downstream effector driving diabetic nephropathy via modulating mitochondrial homeostasis. Methods: A diabetic nephropathy model was generated in wild-type (WT) mice and MAP Kinase phosphatase 1 transgenic (MKP1-TG) mice using STZ injection. Cell experiments were conducted via high-glucose treatment in the human renal mesangial cell line (HRMC). MKP1 overexpression assay was carried out via adenovirus transfection. Renal function was evaluated via ELISA, western blotting, histopathological staining, and immunofluorescence. Mitochondrial function was determined via mitochondrial potential analysis, ROS detection, ATP measurement, mitochondrial permeability transition pore (mPTP) opening evaluation, and immunofluorescence for mitochondrial pro-apoptotic factors. Loss- and gain-of-function assays for mitochondrial fragmentation were performed using a pharmacological agonist and blocker. Western blotting and the pathway blocker were used to establish the signalling pathway in response to MKP1 overexpression in the presence of hyperglycaemia stress. Results: MKP1 was downregulated in the presence of chronic high-glucose stress in vivo and in vitro. However, MKP1 overexpression improved the metabolic parameters, enhanced glucose control, sustained renal function, attenuated kidney oxidative stress, inhibited the renal inflammation response, alleviated HRMC apoptosis, and repressed tubulointerstitial fibrosis. Molecular investigation found that MKP1 overexpression enhanced the resistance of HRMC to the hyperglycaemic injury by abolishing mitochondrial fragmentation. Hyperglycaemia-triggered mitochondrial fragmentation promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway. Interestingly, MKP1 overexpression strongly abrogated mitochondrial fragmentation and sustained mitochondrial homeostasis via inhibiting the JNK-CaMKII-Fis1 pathway. After re-activation of the JNK-CaMKII-Fis1 pathway, the beneficial effects of MKP1 overexpression on mitochondrial protection disappeared. Conclusion: Taken together, our data identified the protective role played by MKP1 in regulating diabetic renal injury via repressing mitochondrial fragmentation and inactivating the JNK-CaMKII-Fis1 pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy.

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“…Previous findings demonstrated that parkin was upregulated in the vascular wall of obese, diabetic and atherosclerotic mice, and parkin-related mitophagy is protective in these disease models [21]. Thus, overexpression or activation of parkin potentially serves as a strategy in treating vascular diseases.…”

Section: Discussionmentioning

confidence: 97%

Parkin Modulates ERRα/eNOS Signaling Pathway in Endothelial Cells

Xia

Yin

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Although a number of reports documented the important role of parkin in mitophagy, emerging evidence also indicated additional functions of parkin besides mitophagy. The present study was undertaken to investigate the role of parkin in the regulation of ERRα/eNOS pathway in endothelial cells (ECs). Methods: Mouse aortic endothelial cells (MAECs) and cardiac muscle HL-1 cells were transfected with parkin plasmid or siRNA. ERRα inhibitor XCT-790, autophagy inhibitor 3-MA and Bafilomycin A1, and caspase inhibitor Z-VAD-FMK were used to block autophagy or apoptosis. Western blotting was performed to examine the protein levels. Flow cytometry was applied to determine the cell apoptosis and ROS production. Mitochondrial membrane potential was measured using JC-1 and TMRM. Immunoprecipitation was performed to confirm the parkin effect on ERRα ubiquitination. Results: Overexpression of parkin resulted in a significant reduction of total-eNOS and p-eNOS in parallel with the downregulation of ERRα (a regulator of eNOS) protein and the enhancement of ERRα ubiquitination. To test the role of ERRα in regulating eNOS in this experimental setting, we treated ECs with ERRα inhibitor and found a decrement of total-eNOS and p-eNOS. On the contrary, overexpression of ERRα increased the levels of total-eNOS and p-eNOS. Meanwhile, parkin overexpression induced mitochondrial dysfunction and cell apoptosis in both ECs and HL-1 cells. Finally, we confirmed that the parkin effect on the regulation of eNOS was independent of the autophagy and apoptosis. Conclusion: These findings suggested that parkin overexpression downregulated eNOS possibly through the ubiquitination of ERRα in endothelial cells.

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NR4A1 contributes to high-fat associated endothelial dysfunction by promoting CaMKII-Parkin-mitophagy pathways

Cited by 42 publications

References 64 publications

DUSP1 recuses diabetic nephropathy via repressing JNK‐Mff‐mitochondrial fission pathways

DUSP1 recuses diabetic nephropathy via repressing JNK‐Mff‐mitochondrial fission pathways

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Parkin Modulates ERRα/eNOS Signaling Pathway in Endothelial Cells

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