NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation

Meng, Xiao‐Ming; Ren, Gui-Ling; Gao, Li; Yang, Qin; Li, Hai-Di; Wang, Weifeng; Huang, Cheng; Zhang, Lei; Lv, Xiongwen; Li, Jun

doi:10.1038/labinvest.2017.120

Cited by 164 publications

(124 citation statements)

References 36 publications

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“…PPBICA not only limited programmed cell death induced by TNF-α and TNF-α plus z-VAD, but also prevented cisplatin-induced necroptosis and apoptosis. Our previous study showed that cisplatin induced the activation of caspase3-dependent apoptosis and RIPK-mediated necroptosis of tubular epithelial cells [2,21,22]. This may lead to loss of tubular epithelial cells and tubule integrity, where adherent junctions are further damaged, back-leaking of tubular fluid and inflammatory responses accelerated, which causes renal dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death

Gao

Liu

Zang

et al. 2018

Laboratory Investigation

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E-cadherin is a major component of tubular adherent proteins that maintain intercellular contacts and cell polarity in epithelial tissue. It is involved in pathological processes of renal cell carcinoma and fibrotic diseases via epithelial-mesenchymal transition. Although studies have shown E-cadherin is significantly downregulated in acute kidney injury (AKI), its function in AKI is unknown. Here, we evaluated cell damage and inflammation in cisplatin-stimulated tubular epithelial cell lines after disrupting E-cadherin and restoring it with PPBICA, a small molecule identified by high-throughput screening. We also determined the therapeutic potential of restoring E-cadherin in vivo. Results show cisplatin reduced E-cadherin expression both in mouse kidney and proximal tubular epithelial cell lines (mTECs). PPBICA restored E-cadherin levels, which increased cell viability while attenuating programmed cell death. This may be mediated via deactivation of the RIPK1/RIPK3 axis and decreased caspase3 cleavage. In addition, PPBICA suppressed inflammatory response in cisplatin-treated mTECs, which correlated with suppressed NF-κB phosphorylation and promoter activity. In contrast, disruption of E-cadherin promoted cell damage and inflammation. PPBICA failed to further attenuate kidney damage in E-cadherin knockdown cells, indicating that PPBICA protects against mTECs through E-cadherin restoration. We also found that peritoneal injection of PPBICA in mice prevented loss of renal function and tubular damage by suppressing NF-κB-driven renal inflammation and RIPK-regulated programmed cell death. This was driven by restoration of E-cadherin in cisplatin nephropathy. Additionally, PPBICA attenuated cisplatin-induced kidney damage in an established AKI model, indicating its therapeutic potential in the treatment of AKI. In conclusion, E-cadherin plays functional roles in tubule integrity, programmed cell death, and renal inflammation. Our results underscore the potential of E-cadherin restoration as a novel therapeutic strategy for AKI.

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Section: Discussionmentioning

confidence: 99%

Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death

Gao

Liu

Zang

et al. 2018

Laboratory Investigation

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“…11 Addi-tionally, NADPH oxidase 4 (NOX4) is a ROS-generating enzyme that participates in inflammatory processes, mainly through the NOX4/ROS pathway. 12,13 In human skin keratinocytes and mouse skin, the production of inflammatory cytokines increases via the NOX4/ROS signaling pathway. 12 Moreover, NOX4 aggravates nephrotoxicity by activating ROS-mediated programmed cell death.…”

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confidence: 99%

“…12 Moreover, NOX4 aggravates nephrotoxicity by activating ROS-mediated programmed cell death. 13 Thus, we hypothesized that NOX4 might regulate NLRP3-dependent pyroptosis via the ROS/ TXNIP axis and, therefore, we aimed to further investigate the mechanism of the role of NOX4 in DR.…”

mentioning

confidence: 99%

miR-590-3pInhibits Pyroptosis in Diabetic Retinopathy by TargetingNLRP1and Inactivating the NOX4 Signaling Pathway

Draga

Zhou

et al. 2019

Invest. Ophthalmol. Vis. Sci.

100

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PURPOSE. To elucidate the mechanism whereby miR-590-3p regulates pyroptosis in diabetic retinopathy (DR). METHODS. Human retinal microvascular endothelial cells (HRMECs) incubated with high glucose (HG) were used to establish cell models, and the expression levels of miR-590-3p, caspase-1, IL-1b, NLRP1, NOX4, TXNIP, NLRP3, and ROS were determined. Additionally, miR-590-3p was altered using a mimic or an inhibitor, and siRNAs targeting NLRP1 and NOX4 were applied to explore the regulatory mechanism of miR-590-3p in DR. The relationships between miR-590-3p and NLRP1/NOX4 also were investigated using a luciferase reporter assay. Furthermore, vitreous tissue samples were collected to confirm pyroptosis in clinical DR. RESULTS. Downregulated miR-590-3p and upregulated NLRP1/NOX4 levels were observed in a cell culture model of DR. Inhibiting miR-590-3p upregulated NLRP1, the NOX4/ROS/TXNIP/ NLRP3 pathway, and caspase-1. NLRP1 and NOX4 were confirmed as direct target genes of miR-590-3p. The overexpression of miR-590-3p or knockdown of NLRP1 and NOX4 increased cell activity and suppressed pyroptosis. Intriguingly, the upregulation of IL-1b induced the downregulation of miR-590-3p by lowering the DNA promoter activity of pri-miR-590. CONCLUSIONS. HG induced pyroptosis in a cell culture model of DR, and the downregulation of miR-590-3p promoted pyroptotic death by targeting NLRP1 and activating the NOX4/ROS/ TXNIP/NLRP3 pathway via an IL-1b-mediated positive feedback loop.

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“…We also evaluated the expression of genes regulated by Hifs including mitochondrial Bnip3, glycolytic Gapdh, and reactive oxygen species (ROS) associated Nox4. Previously, it was shown that Nox4 in particular promotes cisplatin-induced AKI through increased ROS [41]. Further, ROS-mediated stress in general has been implicated in the severity of cisplatininduced kidney injury.…”

Section: Discussionmentioning

confidence: 99%

Prenatal hypoxia increases susceptibility to kidney injury

et al. 2020

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Prenatal hypoxia is a gestational stressor that can result in developmental abnormalities or physiological reprogramming, and often decreases cellular capacity against secondary stress. When a developing fetus is exposed to hypoxia, blood flow is preferentially redirected to vital organs including the brain and heart over other organs including the kidney. Hypoxia-induced injury can lead to structural malformations in the kidney; however, even in the absence of structural lesions, hypoxia can physiologically reprogram the kidney leading to decreased function or increased susceptibility to injury. Our investigation in mice reveals that while prenatal hypoxia does not affect normal development of the kidneys, it primes the kidneys to have an increased susceptibility to kidney injury later in life. We found that our model does not develop structural abnormalities when prenatally exposed to modest 12% O 2 as evident by normal histological characterization and gene expression analysis. Further, adult renal structure and function is comparable to mice exposed to ambient oxygen throughout nephrogenesis. However, after induction of kidney injury with a nephrotoxin (cisplatin), the offspring of mice housed in hypoxia exhibit significantly reduced renal function and proximal tubule damage following injury. We conclude that exposure to prenatal hypoxia in utero physiologically reprograms the kidneys leading to increased susceptibility to injury later in life.

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NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation

Cited by 164 publications

References 36 publications

Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death

Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death

miR-590-3pInhibits Pyroptosis in Diabetic Retinopathy by TargetingNLRP1and Inactivating the NOX4 Signaling Pathway

Prenatal hypoxia increases susceptibility to kidney injury

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