Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation

Zhang, Ji; Zhang, Jiasi; Ni, Haiqiang; Wang, Yanfeng; Katwal, Gaurav; Zhao, Yuanyuan; Sun, Kailun; Wang, Mengqin; Li, Qingwen; Chen, Gen; Miao, Yun; Gong, Nianqiao

doi:10.1038/s41420-021-00425-z

Cited by 31 publications

(27 citation statements)

References 64 publications

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“…Of note, negative regulation of Nrf2 by the XBP1–Hrd1 arm of UPR has been observed in cirrhotic liver models resulting in increased ROS ( 17 ). Similarly, XBP1 via Hrd1 has been shown to modulate the antioxidant function of Nrf2 in ischemia-reperfusion induced acute kidney injury ( 44 ). In these models, Hrd1 mediated Nrf2 inhibition leads to impaired antioxidant response and detrimental increase in ROS.…”

Section: Discussionmentioning

confidence: 99%

Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart

Binder

Nguyen

Collins

et al. 2022

Front. Cardiovasc. Med.

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Endoplasmic Reticulum (ER) stress and oxidative stress have been highly implicated in the pathogenesis of cardiac hypertrophy and heart failure (HF). However, the mechanisms involved in the interplay between these processes in the heart are not fully understood. The present study sought to determine a causative link between Pak2-dependent UPR activation and oxidative stress via Nrf2 regulation under pathological ER stress. We report that sustained ER stress and Pak2 deletion in cardiomyocytes enhance Nrf2 expression. Conversely, AAV9 mediated Pak2 delivery in the heart leads to a significant decrease in Nrf2 levels. Pak2 overexpression enhances the XBP1-Hrd1 UPR axis and ameliorates tunicamycin induced cardiac apoptosis and dysfunction in mice. We found that Pak2 deletion and altered proteostasis render Nrf2 detrimental by switching from its antioxidant role to renin-angiotensin aldosterone system (RAAS) gene regulator. Mechanistically, Pak2 mediated Hrd1 expression targets Nrf2 for ubiquitination and degradation thus preventing its aberrant activation. Moreover, we find a significant increase in Nrf2 with a decrease in Pak2 in human myocardium of dilated heart disease. Using human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we find that Pak2 is able to ameliorate Nrf2 induced RAAS activation under ER stress. These findings demonstrate that Pak2 is a novel Nrf2 regulator in the stressed heart. Activation of XBP1-Hrd1 is attributed to prevent ER stress-induced Nrf2 RAAS component upregulation. This mechanism explains the functional dichotomy of Nrf2 in the stressed heart. Thus, Pak2 regulation of Nrf2 homeostasis may present as a potential therapeutic route to alleviate detrimental ER stress and heart failure.

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Section: Discussionmentioning

confidence: 99%

Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart

Binder

Nguyen

Collins

et al. 2022

Front. Cardiovasc. Med.

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“…Currently, the protective effect of XBP1 downregulation against I/R-induced kidney injury has been reported by Zhang et al . [ 58 ]. In the study, the renal function and pathological score significantly attenuated in XBP1 heterozygous mice subjected to I/R-induced AKI and a higher survival rate compared to the wild-type I/R group.…”

Section: Discussionmentioning

confidence: 99%

The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition

Chen

Jheng

et al. 2022

J Biomed Sci

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Background The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Methods We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia–reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1cKO) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism. Results We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1cKO mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-β1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest. Conclusion The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway.

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“…34 Besides, SYVN1 can enhance I/R induced renal epithelial injury by mediating NRF2 ubiquitylation and degradation. 35 Furthermore, SYVN1 participates in ER-associated degradation of unfolded/misfolded proteins, which is linked to brain ischaemia. 36…”

Section: Discussionmentioning

confidence: 99%

“…SYVN1 mediates the ubiquitination and degradation of glutathione peroxidase 5 (GPX5), increasing the generation of ROS and apoptosis of cardiomyocytes 34 . Besides, SYVN1 can enhance I/R induced renal epithelial injury by mediating NRF2 ubiquitylation and degradation 35 . Furthermore, SYVN1 participates in ER‐associated degradation of unfolded/misfolded proteins, which is linked to brain ischaemia 36 .…”

Section: Discussionmentioning

confidence: 99%

LncRNA MIAT enhances cerebral ischaemia/reperfusion injury in rat model via interacting with EGLN2 and reduces its ubiquitin‐mediated degradation

Wang

et al. 2021

J Cellular Molecular Medi

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Long non-coding RNA (lncRNA) MIAT (myocardial infarction associated transcript) has been characterized as a functional lncRNA modulating cerebral ischaemic/reperfusion (I/R) injury. However, the underlying mechanisms remain poorly understood.This study explored the functional partners of MIAT in primary rat neurons and their regulation on I/R injury. Sprague-Dawley rats were used to construct middle cerebral artery occlusion (MCAO) models. Their cerebral cortical neurons were used for in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) models. Results showed that MIAT interacted with EGLN2 in rat cortical neurons. MIAT overexpression or knockdown did not alter EGLN2 transcription. In contrast, MIAT overexpression increased EGLN2 stability after I/R injury via reducing its ubiquitin-mediated degradation. EGLN2 was a substrate of MDM2, a ubiquitin E3 ligase. MDM2 interacted with the N-terminal of EGLN2 and mediated its K48-linked poly-ubiquitination, thereby facilitating its proteasomal degradation. MIAT knockdown enhanced the interaction and reduced EGLN2 stability. MIAT overexpression enhanced infarct volume and induced a higher ratio of neuronal apoptosis. EGLN2 knockdown significantly reversed the injury. MIAT overexpression reduced oxidative pentose phosphate pathway flux and increased oxidized/reduced glutathione ratio, the effects of which were abrogated by EGLN2 knockdown. In conclusion, MIAT might act as a stabilizer of EGLN2 via reducing MDM2 mediated K48 poly-ubiquitination. MIAT-EGLN2 axis exacerbates I/R injury via altering redox homeostasis in neurons.

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Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation

Cited by 31 publications

References 64 publications

Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart

Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart

The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition

LncRNA MIAT enhances cerebral ischaemia/reperfusion injury in rat model via interacting with EGLN2 and reduces its ubiquitin‐mediated degradation

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