Down-regulating XBP1s alleviates hypoxia/reoxygenation injury of renal tubular epithelial cells by inhibiting ITPR-mediated mitochondrial dysfunction

Ni Haiqiang; Peng Xuan; Gu Shiqi; Gong Nianqiao

doi:10.3969/j.issn.1674-7445.2023198

Volume 15 Issue 2

Mar. 2024

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Ni Haiqiang, Peng Xuan, Gu Shiqi, et al. Down-regulating XBP1s alleviates hypoxia/reoxygenation injury of renal tubular epithelial cells by inhibiting ITPR-mediated mitochondrial dysfunction[J]. ORGAN TRANSPLANTATION, 2024, 15(2): 220-228. doi: 10.3969/j.issn.1674-7445.2023198

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Down-regulating XBP1s alleviates hypoxia/reoxygenation injury of renal tubular epithelial cells by inhibiting ITPR-mediated mitochondrial dysfunction

doi: 10.3969/j.issn.1674-7445.2023198

Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, Key Laboratory of Organ Transplantation of National Health Commission of China, Key Laboratory of Organ Transplantation of Chinese Academy of Medical Sciences, Wuhan 430030, China

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Corresponding author: Gong Nianqiao, Email: nqgong@tjh.tjmu.edu.cn
Received Date: 2023-10-07
Available Online: 2024-01-05
Publish Date: 2024-03-15

Abstract

Abstract

Objective To evaluate the effect of spliced X-box binding protein 1 (XBP1s) on hypoxia/reoxygenation (H/R) injury of mouse renal tubular epithelial cells and unravel underlying mechanism. Methods Mouse renal tubular epithelial cells were divided into adenovirus negative control group (Ad-shNC group), targeted silencing XBP1s adenovirus group (Ad-shXBP1s group), Ad-shNC+H/R group and Ad-shXBP1s+H/R group. The apoptosis level, mitochondrial reactive oxygen activity, mitochondrial membrane potential and mitochondrial calcium ion level were detected in each group. Chromatin immunocoprecipitation followed by sequencing (ChIP-seq) was employed to analyze the binding sites of XBP1s in regulating the inositol 1,4,5-trisphosphate receptor (ITPR) family. The expression levels of XBP1s and ITPR family messenger RNA (mRNA) and protein were determined in each group. Results Compared with the Ad-shNC group, the apoptosis level was higher, mitochondrial reactive oxygen species level was increased, mitochondrial membrane potential was decreased and mitochondrial calcium ion level was elevated in the Ad-shNC+H/R group. Compared with the Ad-shNC+H/R group, the apoptosis level was lower, mitochondrial reactive oxygen species level was decreased, mitochondrial membrane potential was elevated, and mitochondrial calcium ion level was decreased in the Ad-shXBP1s+H/R group (all P<0.05). Compared with the Ad-shNC group, relative expression levels of XBP1s, ITPR1, ITPR2 and ITPR3 mRNAs and proteins were down-regulated in the Ad-shXBP1s group (all P<0.05). Compared with the Ad-shNC group, relative expression levels of XBP1s, ITPR1, ITPR2 and ITPR3 proteins were up-regulated in the Ad-shNC+H/R group. Compared with the Ad-shNC+H/R group, relative expression levels of XBP1s, ITPR1, ITPR2 and ITPR3 were down-regulated in the Ad-shXBP1s+H/R group (all P<0.05). ChIP-seq results showed that XBP1s could bind to the promoter and exon of ITPR1, the exon of ITPR2, and the exon of ITPR3. Conclusions XBP1s may affect mitochondria-associated endoplasmic reticulum membrane structure and function by directly regulating ITPR transcription and translation. Down-regulating XBP1s may inhibit ITPR expression and mitigate mitochondrial damage.

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Down-regulating XBP1s alleviates hypoxia/reoxygenation injury of renal tubular epithelial cells by inhibiting ITPR-mediated mitochondrial dysfunction

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Down-regulating XBP1s alleviates hypoxia/reoxygenation injury of renal tubular epithelial cells by inhibiting ITPR-mediated mitochondrial dysfunction

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