TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

Zhou, Jun; Fan, Yu; Zhong, Jiying; Huang, Zhenxing; Huang, Teng; Shi, Lin; Chen, Hongtao

doi:10.1111/jcmm.13585

Cited by 43 publications

(29 citation statements)

References 55 publications

(103 reference statements)

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“…Both serum deprivation and hypoxia resulted in a significant decline of SQSTM1/p62 content along with concomitant impairments of p38 signaling, MRPL12 level, mtDNA expression, and OXPHOS activity, whereas replenishment of SQSTM1/p62 effectively ameliorated such abnormalities ( Figure 5 ). Furthermore, energy stresses are known to induce the degradation of SQSTM1/p62 by inspiring autophagic flux ( Kaushal and Shah, 2016 ; Zhou et al., 2018 ). Although the role of autophagic degradation could not be excluded, the decreased mRNA level of SQSTM1/p62 indicated that a transcriptional adapting mechanism of SQSTM1/p62 might exist as well ( Figures 6 C and 6L).…”

Section: Discussionmentioning

confidence: 99%

SQSTM1/p62 Controls mtDNA Expression and Participates in Mitochondrial Energetic Adaption via MRPL12

Zhu

et al. 2020

iScience

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Summary Mitochondrial DNA (mtDNA) encodes thirteen core components of OXPHOS complexes, and its steady expression is crucial for cellular energy homeostasis. However, the regulation of mtDNA expression machinery, along with its sensing mechanism to energetic stresses, is not fully understood. Here, we identified SQSTM1/p62 as an important regulator of mtDNA expression machinery, which could effectively induce mtDNA expression and the effects were mediated by p38-dependent upregulation of mitochondrial ribosomal protein L12 (MRPL12) in renal tubular epithelial cells (TECs), a highly energy-demanding cell type related to OXPHOS. We further identified a direct binding site within the MRPL12 promoter to ATF2, the downstream effector of p38. Besides, SQSTM1/p62-induced mtDNA expression is involved in both serum deprivation and hypoxia-induced mitochondrial response, which was further highlighted by kidney injury phenotype of TECs-specific SQSTM1/p62 knockout mice. Collectively, these data suggest that SQSTM1/p62 is a key regulator and energetic sensor of mtDNA expression machinery.

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Section: Discussionmentioning

confidence: 99%

SQSTM1/p62 Controls mtDNA Expression and Participates in Mitochondrial Energetic Adaption via MRPL12

Zhu

et al. 2020

iScience

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“…In a very recent study, lipopolysaccharide (LPS)-induced podocyte injury suppressed the expression of long non-coding RNA-taurine-upregulated gene 1 (TUG1), and TUG1 overexpression enhanced the level of p-MAPK/MAPK and induced autophagy, thus protecting against LPS-induced podocyte injury [186]. Additionally, in cisplatin nephrotoxicity, increased expression of TGF-β-activated kinase 1 (TAK1) resulted in phosphorylation of p38 and ERK, which enhanced excessive autophagy and caused more severe renal injury [187]. In a study related to aristolochic acid (AA)-induced nephropathy, AA treatment induced autophagy and increased ERK1/2 activity and pharmacological inhibition of ERK1/2 phosphorylation with U0126 reduced AAI-induced autophagy and increased apoptosis [188].…”

Section: Mapk/jnk/dapk-mediated Autophagy Induction and Kidney Injurymentioning

confidence: 99%

Autophagy Function and Regulation in Kidney Disease

et al. 2020

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Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

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“…CaMKII mediated ERK1/2 activation in response to Ca 2+ -mobilizing stimuli [43]. Study has found that the toxicity of cisplatin was associated with the activation of ERK1/2 protein [44,45]. These studies provide potent evidence that Ca 2+ /CaMKII/ERK1/2 signaling pathway is a therapeutic target for treating CINV.…”

Section: Discussionmentioning

confidence: 79%

The Antiemetic Effect of Xiao-Ban-Xia-Tang Formula is Associated With Regulating CaM/CaMKII/ERK1/2 Signaling Pathway in Cisplatin and 1-phenylbiguanide Hydrochloride Induced Rat Pica Models

Xia¹,

Xian²,

Feng³

et al. 2020

Preprint

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Background: Xiao-Ban-Xia-Tang (XBXT) formula is a traditional Chinese herbal formula for treating emesis. Chemotherapy-induced nausea and vomiting (CINV) are serious side effects of chemotherapy, which was closely related to the activation of 5-hydroxytryptamine 3 receptor (5-HT3R). In this paper, the effect of XBXT on cisplatin- and 1-phenylbiguanide hydrochloride (1-PBG, a selective 5-HT3R agonist)- induced pica behavior in male Wistar rats and inhibition of calmodulin/calmodulin-dependent protein kinase II/extracellular signal-regulated kinase 1/2 (CaM/CaMKII/ERK1/2) signaling pathway were investigated. Methods: XBXT (1.6 g/kg, twice daily) was orally administered from day 1 after intraperitoneal injection of cisplatin (6 mg/kg) and 1-PBG (25 mg/kg) to day 3. Pica behavior (consumption of kaolin, a type of clay) was recorded every 24 h. The expression and co-localization of CaM and 5-HT3R in small intestine and brain were detected by immunofluorescence. The expression of CaMKII, pCaMKII, ERK1/2, and pERK1/2 proteins were detected by Western blot. Results: XBXT treatment significantly decreased kaolin ingestion (pica) of rats after treatment of cisplatin and 1-PBG during both 0 - 24 h (respectively, from 1.57 g to 0.87 g; from 1.04 g to 0.11 g) and 0 - 72 h (respectively, from 2.98 g to 1.85 g; from 2.29 g to 0.35 g) periods. The fluorescence expression of CaM and 5-HT3R and expression of CaMKII, pCaMKII, ERK1/2 and pERK1/2 in the small intestine and brain of cisplatin- and 1-PBG-treated rats were remarkably suppressed by XBXT.Conclusions: The present study implies that inhibiting CaM/CaMKII/ERK1/2 signaling is an underlying mechanism of XBXT for treating CINV. These insights provide an experimental basis of XBXT for the clinical treatment of CINV.

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TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

Cited by 43 publications

References 55 publications

SQSTM1/p62 Controls mtDNA Expression and Participates in Mitochondrial Energetic Adaption via MRPL12

SQSTM1/p62 Controls mtDNA Expression and Participates in Mitochondrial Energetic Adaption via MRPL12

Autophagy Function and Regulation in Kidney Disease

The Antiemetic Effect of Xiao-Ban-Xia-Tang Formula is Associated With Regulating CaM/CaMKII/ERK1/2 Signaling Pathway in Cisplatin and 1-phenylbiguanide Hydrochloride Induced Rat Pica Models

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