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

Lin, Qiaoxuan; Ma, Yiqiong; Chen, Zhaowei; Hu, Jijia; Cheng, Chen; Fan, Yanqin; Liang, Wei; Ding, Guohua

doi:10.3892/ijmm.2020.4508

Cited by 25 publications

(26 citation statements)

References 41 publications

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“…Conditionally immortalized human podocytes (HPC) were provided by Dr. Moin A. Saleem (Academic Renal Unit, Southmead Hospital, Bristol, United Kingdom) and cultured in RPMI 1640 medium (SH30809.01, HyClone, United States) supplemented with 10% fetal bovine serum (FBS, 10100; Gibco, United States), penicillin G (100 U/ml) -streptomycin (100 μg/ml) (15140122; Life, United States), 1×insulin transferrin-selenium (ITS, 41400045; Life, United States) at 33°C for proliferation. When the density of HPC reached 70–80%, the cells were transferred to 37°C with an ITS-free medium for differentiation ( Fan et al, 2019 ; Hu et al, 2019 ; Lin et al, 2020 ). The differentiated HPC were cultured using different mediums (normal glucose, N = 5 mM d -glucose; mannitol, MA = 5 mM D-glucose+20 mM mannitol; high glucose, HG = 25 mM d -glucose) for 24 h or 36 h; The PERK-inhibited HPC were treated with 20 µM PERK phosphorylation inhibitor (GSK2656157; Selleck, United States).…”

Section: Methodsmentioning

confidence: 99%

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

Cao¹,

Chen²,

Hu³

et al. 2021

Front. Cell Dev. Biol.

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The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD.

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Section: Methodsmentioning

confidence: 99%

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

Cao¹,

Chen²,

Hu³

et al. 2021

Front. Cell Dev. Biol.

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“…Similarly, numerous recent studies highlighted the beneficial effects of antioxidants or other compounds against renal injuries implicating AMPK/NOX4/ROS [133][134][135][136][137][138][139]. Furthermore, two independent studies reported that Sestrin-2 mediated activation of AMPK inhibits ROS production, podocyte impairment in the hyperglycemic condition, and suppresses NOX4 in glomerular mesangial cells [140,141]. p53 and proapoptotic protein PUMA (p53-up-regulated modulator of apoptosis) in diabetic podocytes and glomeruli are promoted by AMPK/NOX4 dysregulation and reversed by AICAR treatment [32].…”

Section: Ampk and Oxidative Stressmentioning

confidence: 96%

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

Juszczak

Caron

Mathew

et al. 2020

IJMS

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Chronic kidney disease (CKD) is prevalent in 9.1% of the global population and is a significant public health problem associated with increased morbidity and mortality. CKD is associated with highly prevalent physiological and metabolic disturbances such as hypertension, obesity, insulin resistance, cardiovascular disease, and aging, which are also risk factors for CKD pathogenesis and progression. Podocytes and proximal tubular cells of the kidney strongly express AMP-activated protein kinase (AMPK). AMPK plays essential roles in glucose and lipid metabolism, cell survival, growth, and inflammation. Thus, metabolic disease-induced renal diseases like obesity-related and diabetic chronic kidney disease demonstrate dysregulated AMPK in the kidney. Activating AMPK ameliorates the pathological and phenotypical features of both diseases. As a metabolic sensor, AMPK regulates active tubular transport and helps renal cells to survive low energy states. AMPK also exerts a key role in mitochondrial homeostasis and is known to regulate autophagy in mammalian cells. While the nutrient-sensing role of AMPK is critical in determining the fate of renal cells, the role of AMPK in kidney autophagy and mitochondrial quality control leading to pathology in metabolic disease-related CKD is not very clear and needs further investigation. This review highlights the crucial role of AMPK in renal cell dysfunction associated with metabolic diseases and aims to expand therapeutic strategies by understanding the molecular and cellular processes underlying CKD.

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“…This imposes a significant energy demand on podocytes, which in turn requires maintaining an adequate mitochondrial number and their proper function. The interest in understanding the mechanisms behind podocyte damage in DN has highlighted the crucial role of mitochondria ( 9-11 ). Mitochondria are key intracellular organelles, which control energy metabolism and are essential for the production and generation of cellular adenosine triphosphate (ATP), through oxidative phosphorylation.…”

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confidence: 99%

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

2021

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Diabetic Nephropathy (DN) is the leading cause of kidney failure, with an increasing incidence worldwide. Mitochondrial dysfunction is known to occur in DN and has been implicated in the underlying pathogenesis of disease. These complex organelles have an array of important cellular functions and involvement in signalling pathways; and understanding the intricacies of these responses in health, as well as how they are damaged in disease, is likely to highlight novel therapeutic avenues. A key cell type damaged early in DN is the podocyte and increasing studies have focused on investigating the role of mitochondria in podocyte injury. This review will summarise what is known about podocyte mitochondrial dynamics in DN, with a particular focus on bioenergetic pathways, highlighting key studies in this field and potential opportunities to target, enhance or protect podocyte mitochondrial function in the treatment of DN.

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

Cited by 25 publications

References 41 publications

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

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