SIRT3 prevents angiotensin II-induced renal tubular epithelial-mesenchymal transition by ameliorating oxidative stress and mitochondrial dysfunction

He, Ping; Li, Zhuoming; Yue, Zhongbao; Gao, Hui; Feng, Guoshuai; Wang, Panxia; Huang, Yi; Luo, Wenwei; Hong, HuiQi; Liu, Liang; Chen, Shao‐Rui; Liu, Peiqing

doi:10.1016/j.mce.2017.04.027

Cited by 35 publications

(23 citation statements)

References 44 publications

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“…Morigi et al found that activation of Sirt3 attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury [ 7 ], and the results were confirmed by Liu et al [ 8 ]. Another study found Sirt3 prevents renal tubulointerstitial fibrosis by ameliorating oxidative stress and mitochondrial dysfunction in an angiotensin II-induced kidney injury model [ 9 ]. Our newly study also found Sirt3 activation ameliorates kidney injury induced by hypertension [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Sirtuin 3 deficiency aggravates contrast-induced acute kidney injury

Zhang¹,

Liu²,

Li³

et al. 2018

J Transl Med

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BackgroundSirtuin 3 (Sirt3) is a key regulator of energy metabolism and oxidative stress. To investigate the role of Sirt3 in contrast-induced acute kidney injury (CIAKI), we established the model both in vivo and in vitro to explore the potential mechanisms.MethodsIn vivo, we established CIAKI models in wild-type (WT) and Sirt3-knockout (Sirt3-KO) mice. Blood urea nitrogen (BUN) and serum creatinine (Scr) were detected by enzyme-linked immunosorbent assay, Glomerular Filtration Rate (GFR) and creatinine clearance were also investigated. We detected the production of reactive oxygen species (ROS) via 2′7′-dichlorodihydro-fluorescein diacetate. The expressions of Sirt3, oxidative stress and apoptosis related markers (MnSOD, Catalase, Acetyl-MnSOD K68, Nox4, Bax, Bcl-2 and Caspase3) were measured and analyzed. In addition, we observed the effect of nicotinamide riboside (NR) on CIAKI in WT and Sirt3-KO mice. In vitro, Sirt3 was knocked out by siRNA transfection method in HK-2 cells. Sirt3, ROS, oxidative stress and apoptosis markers in HK-2 cells were also measured.ResultsOur data demonstrated that the levels of Scr and BUN in Sirt3-KO mice were increased while the levels of the GFR and creatinine clearance were decreased in CIAKI mice. In Sirt3-KO or siRNA groups, the activities of MnSOD and Catalase were markedly down-regulated. Also, the expression of Caspase3 were markedly increased and the ratio of Bcl-2/Bax was decreased, while the ROS level was increased in Sirt3 deficiency groups. NR ameliorated CIAKI in WT mice but not in Sirt3-KO mice.ConclusionOur results suggest that Sirt3 deficiency aggravates contrast-induced acute kidney injury. Sirt3 is critical in NR-mediated renoprotection in CIAKI.

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Section: Introductionmentioning

confidence: 99%

Sirtuin 3 deficiency aggravates contrast-induced acute kidney injury

Zhang¹,

Liu²,

Li³

et al. 2018

J Transl Med

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“…Recent studies prove the potential renoprotective role of several intrinsic modulation factors that are closely related to mitochondrial function. Either downregulation of dynamin-related protein 1 17 or upregulation of NAD-dependent deacetylase sirtuin-3, mitochondrial 18 or TNF receptor associated protein 1 19 could have a protective effect on mitochondrial function in TECs and ameliorate renal fibrosis.Please spell out DRP117, SIRT318 and TRAP1in text, as it is mentioned only once.DRP1 stands for dynamin-related protein 1SIRT3 stands for NAD-dependent deacetylase sirtuin-3, mitochondrialTRAP1 stands for TNF receptor associated protein 1 (TRAP1)…”

Section: What Are the Intracellular Changes Of Tecs Upon Injury?mentioning

confidence: 99%

Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury

2018

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Renal fibrosis, especially tubulointerstitial fibrosis, is the inevitable outcome of all progressive chronic kidney diseases (CKDs) and exerts a great health burden worldwide. For a long time, interests in renal fibrosis have been concentrated on fibroblasts and myofibroblasts. However, in recent years, growing numbers of studies have focused on the role of tubular epithelial cells (TECs). TECs, rather than a victim or bystander, are probably a neglected mediator in renal fibrosis, responding to a variety of injuries. The maladaptive repair mechanisms of TECs may be the key point in this process. In this review, we will focus on the role of TECs in tubulointerstitial fibrosis. We will follow the fate of a tubular cell and depict the intracellular changes after injury. We will then discuss how the repair mechanism of tubular cells becomes maladaptive, and we will finally discuss the intercellular crosstalk in the interstitium that ultimately proceeds tubulointerstitial fibrosis.

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“…We anticipate that other cell types in kidney tissues including mesangial cells and podocytes may also utilize this signalling pathway. However, this research is to examine the role of Ang II-TLR4-STAT3 axis in the epithelial-to-mesenchymal transition in kidney injuries, as reduction of Ang II-induced renal fibrosis has been associated with a reduction of the epithelial-to-mesenchymal transition (He et al, 2018;Hu et al, 2018;Wang et al, 2018). Such experiments are important to better understand how STAT3 mediates epithelial loss and phenotype change, as well tubular atrophy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of STAT3 activation mediated by toll‐like receptor 4 attenuates angiotensin II‐induced renal fibrosis and dysfunction

Zou

Wang

et al. 2019

British J Pharmacology

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Background and Purpose Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood. Experimental Approach C57BL/6 mice were treated with angiotensin II by subcutaneous infusion for 1 month to develop nephropathy. Mice were treated with either adeno‐associated virus expressing STAT3 shRNA or STAT3 inhibitor, S3I‐201. Human archival kidney samples from five patients with hypertension and five individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I‐201 in the renal proximal tubular cell line, NRK52E, after exposure to angiotensin II. Key Results Angiotensin II activated STAT3 in kidney epithelial cells through engaging toll‐like receptor 4 (TLR4) and JAK2, which was independent of IL‐6/gp130 and angiotensin AT1 receptors. Angiotensin II‐mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by the low MW compound S3I‐201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension. Conclusions and Implications Our study reveals a novel mechanism of STAT3 activation, induced by angiotensin II, in kidney tissues and highlights a translational significance of a STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.

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SIRT3 prevents angiotensin II-induced renal tubular epithelial-mesenchymal transition by ameliorating oxidative stress and mitochondrial dysfunction

Cited by 35 publications

References 44 publications

Sirtuin 3 deficiency aggravates contrast-induced acute kidney injury

Sirtuin 3 deficiency aggravates contrast-induced acute kidney injury

Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury

Inhibition of STAT3 activation mediated by toll‐like receptor 4 attenuates angiotensin II‐induced renal fibrosis and dysfunction

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