NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy
| Autor: | Jisheng Zhang, Qin Dai, Min Xu, Jianxun Feng, Junqin Sheng, Hongyan Li, Chang Lu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mff Physiology Ubiquitin-Protein Ligases NR4A1 Diabetic renal damage Kidney medicine.disease_cause Mitochondrial Dynamics Mitochondrial Membrane Transport Proteins Parkin lcsh:Physiology Diabetes Mellitus Experimental Mitochondrial Proteins lcsh:Biochemistry Mice 03 medical and health sciences Mitophagy Nuclear Receptor Subfamily 4 Group A Member 1 Renal fibrosis medicine Animals Humans Diabetic Nephropathies lcsh:QD415-436 RNA Small Interfering Membrane Potential Mitochondrial Mice Knockout lcsh:QP1-981 Mitochondrial Permeability Transition Pore Chemistry Mitochondrial fission Membrane Proteins Cell biology Mice Inbred C57BL Blot 030104 developmental biology Apoptosis RNA Interference Tumor Suppressor Protein p53 Signal transduction Reactive Oxygen Species Oxidative stress Signal Transduction |
| Zdroj: | Cellular Physiology and Biochemistry, Vol 48, Iss 4, Pp 1675-1693 (2018) |
| ISSN: | 1421-9778 1015-8987 |
| Popis: | Background/Aims: Disrupted mitochondrial dynamics, including excessive mitochondrial fission and mitophagy arrest, has been identified as a pathogenic factor in diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation and mitophagy arrest in the setting of DN remains unknown. Methods: Wild-type (WT) mice and NR4A1 knockout (NR4A1-KO) mice were used to establish a DN model. Mitochondrial fission and mitophagy were evaluated by western blotting and immunofluorescence. Mitochondrial function was assessed by JC-1 staining, the mPTP opening assay, immunofluorescence and western blotting. Renal histopathology and morphometric analyses were conducted via H&E, Masson and PASM staining. Kidney function was evaluated via ELISA, western blotting and qPCR. Results: In the present study, we found that nuclear receptor subfamily 4 group A member 1 (NR4A1) was actually activated by a chronic hyperglycemic stimulus. Higher NR4A1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, increased NR4A1 expression activated p53, and the latter selectively stimulated mitochondrial fission and inhibited mitophagy by modulating Mff and Parkin transcription. Excessive Mff-related mitochondrial fission caused 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. In addition, defective Parkin-mediated mitophagy repressed cellular ATP production and failed to correct the uncontrolled mitochondrial fission. However, NR4A1 knockdown interrupted the Mff-related mitochondrial fission and recused Parkin-mediated mitophagy, reducing the hyperglycemia-mediated mitochondrial damage and thus improving renal function. Conclusion: Overall, we have shown that NR4A1 functions as a novel malefactor in diabetic renal damage and operates by synchronously enhancing Mff-related mitochondrial fission and repressing Parkin-mediated mitophagy. Thus, finding strategies to regulate the balance of the NR4A1-p53 signaling pathway and mitochondrial homeostasis may be a therapeutic option for treating diabetic nephropathy in clinical practice. |
| Databáze: | OpenAIRE |
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