Sirt6 deficiency results in progression of glomerular injury in the kidney

Huang, Wen; Liu, Hua; Zhu, Shuang; Woodson, Michael; Liu, Rong; Tilton, Ronald G.; Miller, Jordan D.; Zhang, Wenbo

doi:10.18632/aging.101214

Cited by 55 publications

(45 citation statements)

References 46 publications

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“…The results of SP assay also obtained similar results. Recent study has shown that SIRT6 was closely related to the normal physiological function of the kidney [33]. Deletion of SIRT6 expression in mouse kidney could lead to progressive nephritis, glomerular hypertrophy, loss of podocyte structure and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

et al. 2019

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Sirtuin 6 (SIRT6) has the function of regulating autophagy. The aim of this study was to investigate the mechanism through which SIRT6 relieved acute kidney injury (AKI) caused by sepsis. The AKI model was established with lipopolysaccharides (LPS) using mice. Hematoxylin-eosin (HE) staining and streptavidin-perosidase (SP) staining was used to observe kidney tissue and test SIRT6 and LC3B proteins in kidney. Enzyme-linked immunosorbent assay (ELISA) was performed to detected the tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations. Cell counting kit-8 (CCK-8) assay and flow cytometry were carried out to test the cell viability and apoptosis rate respectively. Protein and mRNA were determined by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR). AKI induced by LPS had self-repairing ability. At 12 h after modeling, the expression levels of TNF-α, IL-6, SIRT6 and LC3B-II/LC3B-I were first significantly increased and were then significantly decreased at 48 h after modeling. LPS inhibited the growth of HK-2 cells and promoted the expressions of TNF-α, IL-6, SIRT6 and LC3B. Overexpression of SIRT6 down-regulated the secretion of TNF-α and IL-6 induced by LPS. SIRT6 overexpression inhibited apoptosis induced by LPS and promoted autophagy in HK-2 cells. Silencing of the SIRT6 gene not only promoted the secretion of TNF-α and IL-6 by HK-2 cells, but also promoted apoptosis and reduced autophagy. LPS up-regulated the expression of SIRT6 gene in HK-2 cells. Overexpression of the SIRT6 gene could inhibit apoptosis and induce autophagy, which might be involved in repairing kidney damage caused by LPS.

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Section: Discussionmentioning

confidence: 99%

Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

et al. 2019

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“…Sirtuins are a family of NAD-dependent histone deacetylases that contain seven enzymatic members in mammals (Sirt1–7) with diverse cellular localizations and functions [ 31 , 32 ]. Sirt1, Sirt6 and Sirt7 mainly reside in the nucleus and regulate transcription by targeting transcription factors, co-factors or histones; Sirt3, Sirt4 and Sirt5 are predominantly localized within the mitochondria and may regulate mitochondrial energy metabolism; and Sirt2 is primarily found in the cytoplasm where it functions as a tubulin deacetylase.…”

Section: Discussionmentioning

confidence: 99%

“…All experimental procedures and use of animals were performed in accordance with the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research. C57BL/6J wild type (WT) mice were purchased from Jackson Laboratory (Bar Harbor, ME), Sirt6 KO and littermate control mice on a C57BL6/129svJ mixed background were generated as described previously [ 32 ], and all mice were maintained on a 12:12 light/dark cycle with food and water available ad libitum .…”

Section: Methodsmentioning

confidence: 99%

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Sirt6 deficiency impairs corneal epithelial wound healing

Zhu

et al. 2018

Aging

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Corneal transparency, dependent on the integrity of epithelial cells, is essential for vision. Corneal epithelial damage is one of the most commonly observed ocular conditions and proper wound healing is necessary for corneal transparency. Sirt6, a histone deacetylase, has been shown to regulate many cellular events including aging and inflammation. However, its specific role in corneal epithelial wound healing remains unknown. Here we demonstrated that Sirt6 was expressed in corneal epithelial cells and its expression decreased with age. In an in vivo corneal epithelial wound healing model, Sirt6 deficiency resulted in delayed and incomplete wound healing and was associated excessive inflammation in the corneal stroma and dysfunction of Notch signaling, leading to keratinization of the corneal epithelium and corneal opacity. Aging Sirt6-deficient mice spontaneously developed corneal keratitis with extensive infiltration of inflammatory cells into the cornea. In vitro experiments demonstrated that primary corneal epithelial cells with Sirt6 downregulation expressed increased basal levels of inflammatory genes and exhibited hyper-inflammatory reactivity to IL-1β and TNFα treatment. These results provide compelling evidence that Sirt6 is a critical regulator of inflammation in the cornea, and is responsible for corneal epithelial wound healing, thus contributing to the maintenance of epithelial integrity and corneal transparency.

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“…Moreover, Liu et al [9] also found that podocyte-specific deletion of Sirt6 mice can cause development a slight albuminuria and podocyte injury at 12 month age, though no significant difference was observed in podocyte-specific deletion of Sirt6 mice compared to their control littermates when followed up to 9 months after birth. Consistently, global Sirt6 deletion in mice induces podocyte injury as evidenced by decreases in slit diaphragm proteins and foot process effacement, eventually leading to proteinuria [39]. These results suggest that Sirt1 and Sirt6 may be potential therapeutic targets for the treatment of patients with aging-related kidney disease.…”

Section: Nad + -Dependent Deacetylases On the Regulation Of Podocyte mentioning

confidence: 58%

Histone Deacetylases Take Center Stage on Regulation of Podocyte Function

et al. 2020

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Background: Podocytes (highly specialized and terminally differentiated epithelial cells) are integral components of the glomerular filtration barrier that are vulnerable to a variety of injuries and, as a result, they undergo a series of changes ranging from hypertrophy to detachment and apoptosis. Podocyte injury is a major determinant in proteinuric kidney disease and identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Although numerous studies have achieved dramatic advances in the understanding of podocyte biology and its relevance to renal injury, few effective and specific therapies are available. Summary: Epigenetic modifications have been proven to play important roles in the pathogenesis of kidney diseases. Among them, histone deacetylase (HDAC)-mediated epigenetic acetylation in the kidney has attracted much attention, which may play multiple roles in both kidney development and the pathogenesis of kidney disease. Recent studies have demonstrated that HDAC protect against podocyte injury by regulation of inflammation, apoptosis, autophagy, mitochondrial function, and insulin resistance. In this review, we summarize recent advances in the understanding of the functions and regulatory mechanisms of HDAC in podocytes and associated proteinuric kidney diseases. In addition, we provide evidence of the potential therapeutic effects of HDAC inhibitors for proteinuric kidney disease. Key Messages: Pharmacological targeting of HDAC-mediated epigenetic processes may open new therapeutic avenues for chronic kidney disease.

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Sirt6 deficiency results in progression of glomerular injury in the kidney

Cited by 55 publications

References 46 publications

Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

Sirt6 deficiency impairs corneal epithelial wound healing

Histone Deacetylases Take Center Stage on Regulation of Podocyte Function

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