Mitophagy regulates macrophage phenotype in diabetic nephropathy rats

Zhao, Yu; Guo, Yinfeng; Jiang, Yuteng; Zhu, Xiaodong; Liu, Yuqiu; Zhang, Xiaoliang

doi:10.1016/j.bbrc.2017.10.088

Cited by 61 publications

(51 citation statements)

References 31 publications

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“…Although a mounting body of data has confirmed that fission activation and mitophagy inhibition are involved in diabetic renal damage via pleiotropic effects [60,68], the upstream regulators of fission and mitophagy have not yet been fully elucidated. Previous studies have suggested that mitochondrial fission is highly governed by Drp1 translocation from the cytoplasm to mitochondria.…”

Section: Discussionmentioning

confidence: 99%

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

Sheng

Dai

et al. 2018

Cell Physiol Biochem

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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.

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Section: Discussionmentioning

confidence: 99%

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

Sheng

Dai

et al. 2018

Cell Physiol Biochem

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“…242 Likewise, the mitophagy level is decreased in M1 macrophages in vivo. 242 Indeed, melatonin has been reported to elevate the mitophagy level in other systems. 241,243,244 However, the exact mechanisms whereby melatonin targets mitophagy remain to be identified.…”

Section: Melatonin Shapes Macrophage Polarization Through Mitochondmentioning

confidence: 99%

“…Mitophagy is an essential intracellular process to eliminate dysfunctional mitochondria, and it is involved in macrophage biology . Mitophagy activation facilitates switching of macrophages from M1 to M2 phenotypes . However, mitophagy inhibition promotes polarizing of macrophages into M1 phenotypes in vitro .…”

Section: Mechanisms Whereby Melatonin Regulates Macrophage Polarizationmentioning

confidence: 99%

“…However, mitophagy inhibition promotes polarizing of macrophages into M1 phenotypes in vitro . Likewise, the mitophagy level is decreased in M1 macrophages in vivo . Indeed, melatonin has been reported to elevate the mitophagy level in other systems .…”

Section: Mechanisms Whereby Melatonin Regulates Macrophage Polarizationmentioning

confidence: 99%

“…240,241 Mitophagy activation facilitates switching of macrophages from M1 to M2 phenotypes. 242 However, mitophagy inhibition promotes polarizing of macrophages into M1 phenotypes in vitro. 242 Likewise, the mitophagy level is decreased in M1 macrophages in vivo.…”

Section: Melatonin Shapes Macrophage Polarization Through Mitochondmentioning

confidence: 99%

See 2 more Smart Citations

Melatonin in macrophage biology: Current understanding and future perspectives

Xia

Chen

Zeng

et al. 2019

Journal of Pineal Research

145

126

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Melatonin is a ubiquitous hormone found in various organisms and highly affects the function of immune cells. In this review, we summarize the current understanding of the significance of melatonin in macrophage biology and the beneficial effects of melatonin in macrophage‐associated diseases. Enzymes associated with synthesis of melatonin, as well as membrane receptors for melatonin, are found in macrophages. Indeed, melatonin influences the phenotype polarization of macrophages. Mechanistically, the roles of melatonin in macrophages are related to several cellular signaling pathways, such as NF‐κB, STATs, and NLRP3/caspase‐1. Notably, miRNAs (eg, miR‐155/‐34a/‐23a), cellular metabolic pathways (eg, α‐KG, HIF‐1α, and ROS), and mitochondrial dynamics and mitophagy are also involved. Thus, melatonin modulates the development and progression of various macrophage‐associated diseases, such as cancer and rheumatoid arthritis. This review provides a better understanding about the importance of melatonin in macrophage biology and macrophage‐associated diseases.

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Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction

et al. 2020

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Obstructive nephropathy favors the progression to chronic kidney disease (CKD), a severe health problem worldwide. The unilateral ureteral obstruction (UUO) model is used to study the development of fibrosis. Impairment of renal mitochondria plays a crucial role in several types of CKD and has been strongly related to fibrosis onset. Nevertheless, in the UUO model, the impairment of mitochondria, their relationship with endoplasmic reticulum (ER) stress induction and the participation of both to induce the fibrotic process remain unclear. In this review, we summarize the current information

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Mitophagy regulates macrophage phenotype in diabetic nephropathy rats

Cited by 61 publications

References 31 publications

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

Melatonin in macrophage biology: Current understanding and future perspectives

Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction

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