Dataset Information

Sirt3 suppresses calcium oxalate-induced renal tubular epithelial cell injury via modification of FoxO3a-mediated autophagy.

ABSTRACT: High oxalic acid and calcium oxalate (CaOx)-induced renal tubular epithelial cell (TEC) injury plays a key role in nephrolithiasis. However, the mechanism remains unknown. Gene array analysis of the mice nephrolithiasis model indicated significant downregulation of sirtuin 3 (Sirt3) and activation of mitogen-activated protein kinase (MAPK) pathway. Kidney biopsy tissues of renal calculi patients also showed decreased Sirt3 expression. Silencing Sirt3 exacerbated oxidative stress and TEC death under CaOx stimulation. Restoring Sirt3 expression by overexpression or enhancing its activity protected renal function and reduced TEC death both in vitro and in vivo. Inhibiting the MAPK pathway resulted in upregulation of Sirt3 expression, preservation of renal function and decreased cell death both in vitro and in vivo. Furthermore, Sirt3 could upregulate FoxO3a activity post-translationally via deacetylation, dephosphorylation and deubiquitination. FoxO3a was found to interact with the promoter region of LC3B and to increase its expression, enhancing TEC autophagy and suppressing cell apoptosis and necrosis. Taken together, our results indicate that the MAPK/Sirt3/FoxO3a pathway modulates renal TEC death and autophagy in TEC injury.

SUBMITTER: Peng Y

PROVIDER: S-EPMC6377683 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Sirt3 suppresses calcium oxalate-induced renal tubular epithelial cell injury via modification of FoxO3a-mediated autophagy.

Peng Yonghan Y Yang Cheng C Shi Xiaolei X Li Ling L Dong Hao H Liu Changcheng C Fang Ziyu Z Wang Zeyu Z Ming Shaoxiong S Liu Min M Xie Bin B Gao Xiaofeng X Sun Yinghao Y

Cell death & disease 20190115 2

High oxalic acid and calcium oxalate (CaOx)-induced renal tubular epithelial cell (TEC) injury plays a key role in nephrolithiasis. However, the mechanism remains unknown. Gene array analysis of the mice nephrolithiasis model indicated significant downregulation of sirtuin 3 (Sirt3) and activation of mitogen-activated protein kinase (MAPK) pathway. Kidney biopsy tissues of renal calculi patients also showed decreased Sirt3 expression. Silencing Sirt3 exacerbated oxidative stress and TEC death un ...[more]

PMID: 30674870

Similar Datasets

Project description:BACKGROUND:Intrarenal calcium oxalate (CaOx) crystals induce inflammation and kidney tubular cell injury, which are processes that involve TLR4/NF-?B signalling. A recent genome-wide gene expression profile analysis of Randall's plaques in CaOx stone patients revealed that the expression of the long noncoding RNA H19 was significantly upregulated. However, to date, its role in kidney CaOx stones has not been reported. METHOD:A Gene Expression Omnibus (GEO) dataset was utilized to analyse gene expression profiles. Luciferase reporter, Western blotting, qRT-PCR, immunofluorescence staining and reactive oxygen species (ROS) assays were employed to study the molecular mechanism of HMGB1/TLR4/NF-?B regulation by H19 and miR-216b. In vitro and in vivo assays were performed to further confirm the proinflammatory and prooxidative stress effects. FINDING:H19 expression was significantly increased and positively correlated with the expression levels of HMGB1, TLR4 and NF-?B in Randall's plaques and glyoxylate-induced CaOx nephrocalcinosis mouse models. H19 interacted with miR-216b and suppressed its expression. Additionally, miR-216b inhibited HMGB1 expression by directly binding its 3'-untranslated region. Moreover, H19 downregulation inhibited HMGB1, TLR4 and NF-?B expression and suppressed CaOx nephrocalcinosis-induced renal tubular epithelial cell injury, NADPH oxidase, and oxidative stress in vivo and in vitro. Interestingly, miR-216b inhibition partially reversed the inhibitory effect of H19 knockdown on HMGB1 expression. INTERPRETATION:We determined that H19 might serve as a facilitator in the process of CaOx nephrocalcinosis-induced oxidative stress and renal tubular epithelial cell injury, and we revealed that the interaction between H19 and miR-216b could exert its effect via the HMGB1/TLR4/NF-?B pathway. FUNDING:This work was supported by the National Nature Science Foundation of China (Nos. 8196030190, 8190033175, 81370805, 81470935, 81900645, 81500534, and 81602236).

Project description:BackgroundAs a common urological disease with a high recurrence rate, nephrolithiasis caused by CaOx may elicit a strong immunologic response. We present a CyTOF-based atlas of the immune landscape in nephrolithiasis models to understand how the immune system contributes to, and is affected by, the underlying response caused by SIRT3 knockout and CaOx inducement.Materials and methodsWe performed a large-scale CyTOF analysis of immune cell abundance profiles in nephrolithiasis. The immunophenotyping data were collected from four different mouse models, including the SIRT3 wild-type or knockout, including and excluding CaOx inducement. Unsupervised analysis strategies, such as SPADE and viSNE, revealed the intrarenal resident immune components and the immune alterations caused by SIRT3 knockout and CaOx-induced renal injury.ResultsAn overview analysis of the immune landscape identified T cells and macrophages as the main immune cell population in nephrolithiasis models. Highly similar phenotypes were observed among CD4+ and CD8+ T cell subsets, including cells expressing Ki67, Ly6C, Siglec-F, and TCRβ. Macrophages expressed a characteristic panel of markers with varied expression levels including MHC II, SIRPα, CD11c, Siglec-F, F4/80, CD64, and CD11b, indicating more subtle differences in marker expression than T cells. The SIRT3KO/CaOx and SIRT3WT/CaOx groups exhibited global differences in the intrarenal immune landscape, whereas only small differences existed between the SIRT3KO/CaOx and SIRT3KO/Ctrl groups. Among the major immune lineages, the response of CD4+ T cells, NK cells, monocytes, and M1 to CaOx inducement was regulated by SIRT3 expression in contrast to the expression changes of B cells, DCs, and granulocytes caused by CaOx inducement. The panel of immune markers influenced by CaOx inducement significantly varied with and without SIRT3 knockout.ConclusionIn a CaOx-induced nephrolithiasis model, SIRT3 has a critical role in regulating the immune system, especially in reducing inflammatory injury. The characteristic panel of altered immune clusters and markers provides novel insights leading to improved prediction and management of nephrolithiasis.

Dataset Information

Sirt3 suppresses calcium oxalate-induced renal tubular epithelial cell injury via modification of FoxO3a-mediated autophagy.

Publications

Sirt3 suppresses calcium oxalate-induced renal tubular epithelial cell injury via modification of FoxO3a-mediated autophagy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets