SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Sundaresan, Nagalingam R.; Bindu, Samik; Pillai, Vinodkumar B.; Samant, Sadhana; Pan, Yong; Huang, Jingyi; Gupta, Madhu; Nagalingam, Raghu S.; Wolfgeher, Donald J.; Verdin, Eric; Gupta, Mahesh P.

doi:10.1128/mcb.00586-15

Cited by 160 publications

(158 citation statements)

References 68 publications

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Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 52%

“…Mitochondrial SIRT3 is reported to control the transformation of fibroblasts into myofibroblasts via suppression of TGF-β1 signaling (87,88). In concordance, SIRT3-deficient, aging mice were found to develop tissue fibrosis of multiple organs, including heart, liver, kidney, and lungs (87). In the lung, SIRT3 deficiency augmented pulmonary fibrosis after asbestos and bleomycin exposure (88,89), and SIRT3 expression is attenuated in skin and lung of systemic sclerosis patients (90).…”

Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 65%

“…Fibrosis results from abnormal tissue repair, and exaggerated remodeling is frequently associated with persistent and/or severe injury and cell apoptosis. Current evidence suggests that mitochondrial dysfunction plays a critical role in the vulnerability to fibrotic conditions (17,19,84,85,87,122,123). Tissue-and cell-specific pathways regulate or respond to mitochondrial function to meet ever-changing physiological needs.…”

Section: Metabolic Dysregulation As a Convergent Event In The Aging Cellmentioning

confidence: 99%

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Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

176

169

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One of the most remarkable medical accomplishments in the last century has been the increasing longevity of the human population. A decrease in birth rates, accompanied by a reduction in mortality among the elderly population, has collectively increased the percentage of the aged population, particularly in developed countries. Globally, it is estimated that the proportion of the population over the age of 60 will increase from 11% to 22% by 2050, and 28% by 2100. Currently, 18% of the US population is over 60 years of age (57 million), which is predicted to rise to 27% (107 million) in 2050 and up to 31% (149 million) by 2100 (1). The aging population has propelled an increase in the overall prevalence of chronic conditions. Several lung diseases, including acute lung injury and asthma, and some infectious diseases, such as pneumonia, increase in severity and mortality with age. Additionally, there has been a significant increase in incidence of chronic lung diseases -including chronic obstructive pulmonary disease, most forms of lung cancer, and idiopathic pulmonary fibrosis (IPF) -resulting in aging-related increases in prevalence.IPF is the most common form of idiopathic interstitial lung diseases. Its overall incidence in the US is 7 to 17 per 100,000 persons with a prevalence between 13.2 and 63 per 100,000 persons (2). A 1996 study initially demonstrated a higher incidence and prevalence of IPF in patients over 65 (3). These observations were confirmed more recently by Raghu et al. (4) and others, using both broad and narrow case-finding criteria for IPF diagnosis. These studies estimated that in the US, the prevalence of IPF increases with age, ranging from 4 per 100,000 for population aged between 18 and 34 years old to 227.2 per 100,000 among those 75 or older (4). This aging-related increase in cumulative incidence and prevalence of IPF has been corroborated by several studies that include populations in Europe and Asia (5-9). Accordingly, the median age at diagnosis of sporadic IPF ranges between 50 and 85 years old, and patients younger than 50 are more commonly associated with familial, rather than sporadic, forms of the disease (2). Mortality rates from IPF are steadily increasing worldwide, and a positive association has also been observed with advanced age (10). Examination of US government health insurance data for people aged 65 and older shows an increasing prevalence of IPF among older age groups (11). These studies confirm the growing concern that aging, and consequently age-related diseases, will drive up health care expenditures. As the elderly population in developed countries is expected to double in the next 25 years, there is an urgent need to understand the pathogenesis of IPF and develop interventions to attenuate or reverse lung fibrosis. The physiology of aging and the lungEvolutionary theories of aging include the concept of selection shadow that permits the accumulation of mutations with late deleterious effects, and the theory of antagonistic pleiotropy, which supports the sele...

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Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 52%

Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 65%

Section: Metabolic Dysregulation As a Convergent Event In The Aging Cellmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

176

169

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“…Furthermore, formation of tissue fibrosis in a number of other organs again depending on the age was demonstrated in the Sirt3-KO mice. The older the Sirt3-KO mouse, the more affected organs were observed, including the lung, kidney, and liver, in contrast to the corresponding age-matched control group [29]. Mice that lack or have reduced expression of SIRT3 also develop pulmonary arterial hypertension.…”

Section: Spontaneous Age-related Organ Fibrosis In Sirtuin 3-deficienmentioning

confidence: 99%

“…Nevertheless, malfunction of SIRT3 is not accompanied by the presence of inflammatory infiltrates, even though mitochondrial damage and the presence of oxidative stress have been detected [30]. Studies on SIRT3 also showed that increased expression of SIRT3 prevents the development of experimentally induced organ fibrosis and promotes the essential role of SIRT3 in maintaining cellular homeostasis of tissues during aging [29,31].…”

Section: Spontaneous Age-related Organ Fibrosis In Sirtuin 3-deficienmentioning

confidence: 99%

Animal Models of Systemic Sclerosis

Štorkánová¹,

Tomčík²

2017

Systemic Sclerosis

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Systemic sclerosis (SSc) is a rare, chronic connective tissue disease affecting the skin, vessels, musculoskeletal system, and internal organs. Despite advances in pharmacotherapy of organ manifestations and new knowledge about the pathogenesis of SSc, there is still no effective universal treatment of this serious disease. The aim of this chapter is to introduce traditional, most commonly used experimental animal models of SSc, clarify their basic pathological mechanism, describe their advantages and limitations, and outline their use in preclinical tests of potential therapeutic agents with subsequent clinical trials in patients with SSc. The existing models have already contributed significantly to preclinical testing of several available biological agents and small molecules, some of which achieved promising results in early clinical studies, and could provide better prospects for patients with this incurable disease.

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Sirtuin 3 is required for the dexmedetomidine‐mediated alleviation of inflammation and oxidative stress in nephritis

Lu,

Li,

2024

Immunity Inflam & Disease

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IntroductionAlthough sirtuin 3 (SIRT3) is known to be involved in dexmedetomidine (DEX)‐mediated alleviation of renal ischemia and reperfusion injury, the influence of the association between DEX and SIRT3 on nephritis development remains unclear. In this study, the role of SIRT3 in DEX‐mediated amelioration of inflammation and oxidative stress in nephritis as well as the possible underlying mechanism were explored in vivo and in vitro.MethodsAn animal model of glomerulonephritis was generated by injecting mice with interferon‐alpha (IFNα)‐expressing adenoviruses, and periodic acid–Schiff staining was then used to reveal pathogenicity‐related changes in the renal tissue. Additionally, human embryonic kidney cells (HEK293) and renal mesangial cells (RMCs) were treated with IFNα to establish cell models of inflammation in vitro.ResultsDEX administration alleviated glomerulonephritis in the animal model and upregulated SIRT3 expression in the renal tissue. SIRT3 knockdown inhibited the renoprotective effects of DEX against nephritis. IFNα induced inflammation, oxidative stress, and apoptosis in the RMCs and HEK293 cells and reduced their growth, as evidenced by the evaluation of cytokine levels (enzyme‐linked immunosorbent assay), reactive oxygen species generation, catalase and superoxide dismutase activities, nuclear factor‐erythroid factor 2‐related factor 2/heme oxygenase‐1 signal transduction, apoptotic cell proportion, and cell viability. In addition to promoting SIRT3 expression, DEX inhibited IFNα‐induced inflammation, oxidative stress, and apoptosis in these cells and promoted their viability. SIRT3 knockdown partially reversed the beneficial effects of DEX on RMCs and HEK293 cells.ConclusionsOur results suggest that DEX exhibits renoprotective activity during nephritis progression, protecting renal cells against inflammatory injury by promoting SIRT3 expression.

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SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Cited by 160 publications

References 68 publications

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Animal Models of Systemic Sclerosis

Sirtuin 3 is required for the dexmedetomidine‐mediated alleviation of inflammation and oxidative stress in nephritis

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