Sirt3 suppresses calcium oxalate-induced renal tubular epithelial cell injury via modification of FoxO3a-mediated autophagy
Authors: Cheng Yang
Yinghao Sun
Zeyu Wang
Yonghan Peng
Xiaolei Shi
Min Liu
Xiaofeng Gao
Ziyu Fang
Changcheng Liu
Hao Dong
Ling Li
Bin Xie
Shaoxiong Ming
Journal: Cell death & disease (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: oxalic acid; calcium oxalate; renal tubular epithelial cell; nephrolithiasis; sirtuin 3
Affiliations: Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, 200433, China., Department of Urology, Zhongshan Hospital, Fudan University; Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China., Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China., Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, OX3 7LD, UK. ., Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, 200433, China. .

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. 

Retracted: Yes

PubPeer comments:
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 2020 retraction. https: www.nature.com articles s41419-020-2318-2 The authors have retracted this article, after publication, because they found that they could not repeat the Annexin V PI flow cytometry apoptosis experiments with the renal tubular epithelial cells. This method is not stable for CaOx-induced tubular epithelial cells injury detection in vitro. Therefore, the flow cytometry results are not reliable. This specifically impacts Figs. 2a, 3a, 4b, e, 6g and 8a. All authors agree with this retraction. , 
 #5 The retraction does not explain why there are so many repeated panel which has nothing to with the method is stable or not. , 
 #6 It does seem problematic for a Retraction notice to warn people against using a particular method to quantify  CaOx-induced tubular epithelial cells injury detection in vitro (because the results are  not stable and  unreliable ). If this is an empirical observation, a peer-reviewed paper would seem the better way to report it. If it is **not** an observation so much as a rationale for the duplication of numerous FACS plots, isn t there a risk of misleading other researchers? ,