Cisplatin-induced macroautophagy occurs prior to apoptosis in proximal tubules in vivo

Inoue, Kosuke; Kuwana, Hitoshi; Shimamura, Yuto; Ogata, Koji; Taniguchi, Yoshinori; Kagawa, Tetsuya; Horino, Taro; Takao, Toshihiro; Morita, Tatsuhito; Sasaki, Sei; Mizushima, Noboru; Terada, Yoshio

doi:10.1007/s10157-009-0254-7

Cited by 84 publications

(89 citation statements)

References 28 publications

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“…We showed that apoptosis of NRK-52E cells incubated under hypoxic conditions was significantly reduced by overexpression of sestrin-2 by caspase-3 activity and TUNEL assay. Our recent report (20) demonstrated that autophagy occurs before apoptosis in renal tubular cells during AKI. However, the role played by autophagy under apoptotic conditions remains controversial.…”

Section: Discussionmentioning

confidence: 90%

“…This is the first study to demonstrate that autophagy and mitophagy are induced, at least partially, by two signaling pathways in renal tubular cells after oxidative stress. We (20) previously using GFP-LC3 transgenic mice to investigate autophagy in kidney tissues during cisplatin nephrotoxicity and demonstrated that autophagy mainly occurred in the proximal tubules. Despite some controversies, most pharmacological, genetic, and knockout studies have supported a renoprotective role for autophagy in renal tubular cells in AKI.…”

Section: Discussionmentioning

confidence: 99%

“…We (20) have previously reported results from a study of autophagy in a mouse model of AKI. Autophagy plays roles in the pathogenesis of many diseases, and, in kidney disease, both beneficial and detrimental effects of autophagy have been reported (19 -22).…”

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confidence: 99%

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Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Imamura

Urushido

Hamada

et al. 2013

American Journal of Physiology-Renal Physiology

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178

125

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Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1␣ and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stressinduced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1␣-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1␣-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.Bcl-2/adenovirus E1B 19 kDa-interacting protein-3; acute kidney injury; autophagy; mitophagy; sestrin-2 ISCHEMIA is the leading cause of acute kidney injury (AKI) in the adult population. Prominent morphological features of ischemic AKI include effacement and loss of the proximal tubule brush border, patchy loss of tubular cells, focal areas of proximal tubular dilation, and increased apoptosis (9). The mechanisms that dictate the survival or death of renal cells under oxidative stress must be more completely understood before novel therapeutic strategies for the treatment of ischemic AKI can be explored. Proximal renal tubular cells have high rates of ATP consumption and are very sensitive to hypoxia; thus, mitochondrial damage is one of the most important factors in determining the survival of these cells (1,43).Autophagy is one of the cellular processes that protect cells from genotoxic stress, oxidative stress, accumulation of misfolded proteins, and nutrient deprivation. We (20) have previously reported results from a study of autophagy in a mouse model of AKI. Autophagy plays roles in the pathogenesis of many diseases, and, in kidney disease, both beneficial and detrimental effects of autophagy have been reported (19 -22). Our understanding of autophagy has expanded greatly in recent years, largely due to the identification...

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Imamura

Urushido

Hamada

et al. 2013

American Journal of Physiology-Renal Physiology

Self Cite

178

125

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“…[15][16][17] These studies mainly used autophagy inhibitors (e.g., 3-methyladenine) or gene knockdown to modulate the activity of autophagy. Autophagy inhibitors are known to inhibit not only autophagy but also inhibit many other degradative pathways (e.g., proteasome, lysosomal function, mitochondrial function, or endocytosis).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Protects the Proximal Tubule from Degeneration and Acute Ischemic Injury

Kimura

Takabatake

Takahashi

et al. 2011

Journal of the American Society of Nephrology

401

416

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Autophagy is a bulk protein degradation system that likely plays an important role in normal proximal tubule function and recovery from acute ischemic kidney injury. Using conditional Atg5 gene deletion to eliminate autophagy in the proximal tubule, we determined whether autophagy prevents accumulation of damaged proteins and organelles with aging and ischemic renal injury. Autophagy-deficient cells accumulated deformed mitochondria and cytoplasmic inclusions, leading to cellular hypertrophy and eventual degeneration not observed in wildtype controls. In autophagydeficient mice, I/R injury increased proximal tubule cell apoptosis with accumulation of p62 and ubiquitin positive cytoplasmic inclusions. Compared with control animals, autophagy-deficient mice exhibited significantly greater elevations in serum urea nitrogen and creatinine. These data suggest that autophagy maintains proximal tubule cell homeostasis and protects against ischemic injury. Enhancing autophagy may provide a novel therapeutic approach to minimize acute kidney injury and slow CKD progression.

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“…The study of autophagy has revealed that autophagy deficiencies under nutrient excess conditions were involved in the pathogenesis of aging-related or metabolic diseases, including kidney disease (85,86). Currently, nephrologists are also entering this exciting field, and it has been revealed that autophagy has a renoprotective effect in a number of animal models including those used for acute kidney injury and aging (86)(87)(88)(89)(90)(91). More specifically, autophagy enhances cell adaptation to hypoxia and maintains podocyte homeostasis in aging mice (86,87).…”

Section: Sirt1 Induces Autophagy By Targeting Autophagy-related Genesmentioning

confidence: 99%

Sirtuin 1: A Target for Kidney Diseases

Kong

Zhou

et al. 2015

Mol Med

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Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD + -dependent histone deacetylase that is necessary for caloric restriction-related lifespan extension. SIRT1, as an intracellular energy sensor, detects the concentration of intracellular NAD + and uses this information to adapt cellular energy output to cellular energy requirements. Previous studies on SIRT1 have confirmed its beneficial effects on cellular immunity to oxidative stress, reduction of fibrosis, suppression of inflammation, inhibition of apoptosis, regulation of metabolism, induction of autophagy and regulation of blood pressure. All of the above biological processes are involved in the pathogenesis of kidney diseases. Therefore, the activation of SIRT1 may become a therapeutic target to improve the clinical outcome of kidney diseases. In this review, we give an overview of SIRT1 and its molecular targets as well as SIRT1-modulated biological processes, with a particular focus on the role of SIRT1 in kidney diseases.

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Cisplatin-induced macroautophagy occurs prior to apoptosis in proximal tubules in vivo

Cited by 84 publications

References 28 publications

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Autophagy Protects the Proximal Tubule from Degeneration and Acute Ischemic Injury

Sirtuin 1: A Target for Kidney Diseases

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