Klotho ameliorates diabetic nephropathy via LKB1-AMPK-PGC1α-mediated renal mitochondrial protection

Lee, Jinho; Tsogbadrakh, Bodokhsuren; Yang, Seung-Hee; Ryu, Hyunjin; Kang, Eun Kyeong; Kang, Min‐Jung; Kang, Hee Gyung; Ahn, Curie; Oh, Kook‐Hwan

doi:10.1016/j.bbrc.2020.10.040

Cited by 30 publications

(26 citation statements)

References 27 publications

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“…A number of studies have provided strong evidence that decreased PGC1α and reduced mitochondrial biogenesis are key features in the development of DKD. PGC1α has been demonstrated to be significantly decreased in the diabetic kidneys (9,45,145,(173)(174)(175). STZ treated rats have decreased PGC1α in renal tubules.…”

Section: Mitochondrial Biogenesis and Mitophagymentioning

confidence: 96%

Mitochondrial Regulation of Diabetic Kidney Disease

2021

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The role and nature of mitochondrial dysfunction in diabetic kidney disease (DKD) has been extensively studied. Yet, the molecular drivers of mitochondrial remodeling in DKD are poorly understood. Diabetic kidney cells exhibit a cascade of mitochondrial dysfunction ranging from changes in mitochondrial morphology to significant alterations in mitochondrial biogenesis, biosynthetic, bioenergetics and production of reactive oxygen species (ROS). How these changes individually or in aggregate contribute to progression of DKD remain to be fully elucidated. Nevertheless, because of the remarkable progress in our basic understanding of the role of mitochondrial biology and its dysfunction in DKD, there is great excitement on future targeted therapies based on improving mitochondrial function in DKD. This review will highlight the latest advances in understanding the nature of mitochondria dysfunction and its role in progression of DKD, and the development of mitochondrial targets that could be potentially used to prevent its progression.

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Section: Mitochondrial Biogenesis and Mitophagymentioning

confidence: 96%

Mitochondrial Regulation of Diabetic Kidney Disease

2021

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“…In addition, the complex interplay between autophagy and apoptosis plays an important role in determining the degree of apoptosis and promoting DR [32]. Increasing evidence shows that when AMPK is activated, mitochondrial function [33] and autophagy [34] are enhanced, and apoptosis is inhibited. Therefore, the regulation of mitochondria and autophagy may be helpful in preventing or treating diabetes-induced retinal photoreceptor degeneration.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of AMPK Prevents Diabetes‐Induced Photoreceptor Cell Degeneration

Song

Bao

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Diabetic retinopathy (DR) is a kind of severe retinal neurodegeneration. The advanced glycation end products (AGEs) affect autophagy, and mitochondrial function is involved in DR. Adenosine-activated protein kinase (AMPK) is an important metabolic sensor that can regulate energy homeostasis in cells. However, the effect of AMPK in DR is still not fully understood. In this study, we investigated the effect of AMPK on diabetes-induced photoreceptor cell degeneration. In vivo, a diabetic mouse model was established by streptozotocin (STZ) injection. Haematoxylin-eosin (HE) staining was used to observe retinal morphology and measure the thicknesses of different layers in the retina. Electroretinogram (ERG) was used to evaluate retinal function. In vitro, 661w cells were treated with AGEs with/without an AMPK agonist (metformin) or AMPK inhibitor (compound C). Flow cytometry and CCK-8 assays were used to analyse apoptosis. Mitochondrial membrane potential was analysed by JC-1. Western blotting and qRT-PCR were used to examine the expression of related proteins and genes, respectively. The wave amplitude and the thickness of the outer nuclear layer were decreased in diabetic mice. The expression of rhodopsin and opsin was also decreased in diabetic mice. In vitro, the percentage of apoptotic cells was increased, the expression of the apoptosis-related protein Bax was increased, and Bcl-2 was decreased after AGE treatment in 661w cells. The expression of the autophagy-related protein LC3 was decreased, and p62 was increased. The mitochondrial-related gene expression and membrane potential were decreased, and mitochondrial morphology was abnormal, as observed by TEM. However, AMPK stimulation ameliorated this effect. These results indicate that AMPK stimulation can delay diabetes-induced photoreceptor degeneration by regulating autophagy and mitochondrial function.

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“…Another biomarker of aging that has received some attention in the context of COPD skeletal muscle impairment is the antiaging hormone α-klotho (hereafter referred to as klotho). Klotho serves as a co-receptor for fibroblast growth factor 23 to activate a variety of fibroblast growth factor receptors throughout the body (Cheikhi et al, 2019), and is necessary for normal mitochondrial function in a variety of tissues (Chen et al, 2020;Lee et al, 2021), including skeletal muscle (Sahu et al, 2018). Various studies have implicated klotho in normal aging of skeletal muscle, with studies showing that reduced circulating levels of klotho in the blood with aging correlate with poor grip strength (Semba et al, 2012), reduced knee extensor strength (Semba et al, 2016), and impaired muscle regeneration (Sahu et al, 2018), amongst other agerelated issues.…”

Section: Chronic Obstructive Pulmonary Disease and Exacerbated Muscle...mentioning

confidence: 99%

Integrating Mechanisms of Exacerbated Atrophy and Other Adverse Skeletal Muscle Impact in COPD

Taivassalo

Hepple

2022

Front. Physiol.

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The normal decline in skeletal muscle mass that occurs with aging is exacerbated in patients with chronic obstructive pulmonary disease (COPD) and contributes to poor health outcomes, including a greater risk of death. There has been controversy about the causes of this exacerbated muscle atrophy, with considerable debate about the degree to which it reflects the very sedentary nature of COPD patients vs. being precipitated by various aspects of the COPD pathophysiology and its most frequent proximate cause, long-term smoking. Consistent with the latter view, recent evidence suggests that exacerbated aging muscle loss with COPD is likely initiated by decades of smoking-induced stress on the neuromuscular junction that predisposes patients to premature failure of muscle reinnervation capacity, accompanied by various alterations in mitochondrial function. Superimposed upon this are various aspects of COPD pathophysiology, such as hypercapnia, hypoxia, and inflammation, that can also contribute to muscle atrophy. This review will summarize the available knowledge concerning the mechanisms contributing to exacerbated aging muscle affect in COPD, consider the potential role of comorbidities using the specific example of chronic kidney disease, and identify emerging molecular mechanisms of muscle impairment, including mitochondrial permeability transition as a mechanism of muscle atrophy, and chronic activation of the aryl hydrocarbon receptor in driving COPD muscle pathophysiology.

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Klotho ameliorates diabetic nephropathy via LKB1-AMPK-PGC1α-mediated renal mitochondrial protection

Cited by 30 publications

References 27 publications

Mitochondrial Regulation of Diabetic Kidney Disease

Mitochondrial Regulation of Diabetic Kidney Disease

Stimulation of AMPK Prevents Diabetes‐Induced Photoreceptor Cell Degeneration

Integrating Mechanisms of Exacerbated Atrophy and Other Adverse Skeletal Muscle Impact in COPD

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