TIMP2 mediates endoplasmic reticulum stress contributing to sepsis‐induced acute kidney injury

Jiang, Nanhui; Huang, Rong; Zhang, Jiahao; Xu, Dongxue; Li, Tianlong; Sun, Zhongyi; Su, L. Joseph; Peng, Zhiyong

doi:10.1096/fj.202101555rr

Cited by 17 publications

(15 citation statements)

References 58 publications

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“…We further compared expression and pathway activity of kidney injury markers across different segments between Con and AAN groups. Four kidney injury markers Fabp1 ( 43 ), Havcr1 ( Kim1 ) ( 44 ), Lcn2 ( 45 ) and Timp2 ( 46 ) were upregulated in AAN ( Figure 4G ). More importantly, AAN group not only showed upregulation of adult tubular stem cell markers Cd24a ( Cd24 ) and Prom1 ( Cd106 ) ( 44 ), but also reactivated nephron progenitor markers Sall1 ( 47 ) and Pax2 ( 44 ).…”

Section: Resultsmentioning

confidence: 99%

Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy

Chen¹,

Luo²,

Wang³

et al. 2022

JCI Insight

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Aristolochic acid nephropathy (AAN) is characterized by acute proximal tubule necrosis and immune cell infiltration, contributing to the global burden of chronic kidney disease and urothelial cancer. Although the proximal tubule has been defined as the primary target of aristolochic acids I (AAI), the mechanistic underpinning of gross renal deterioration caused by AAI has not been explicitly explained, prohibiting effective therapeutic intervention. To this point, we employed integrated single-cell RNA-sequencing, bulk RNA-sequencing, and mass spectrometry-based proteomics to analyze mouse kidney post-acute AAI exposure. Our results revealed a dramatic reduction of proximal tubule epithelial cells, associated with apoptotic and inflammatory pathways, indicating permanent damage beyond repair. We found the enriched development pathways in other nephron segments, suggesting activation of reparative programs triggered by AAI. The divergent response may be attributed to the segment-specific distribution of organic anions channels along the nephron, including OAT1 and OAT3. Moreover, we observed dramatic activation and recruitment of cytotoxic T and macrophage M1 cells, highlighting inflammation as a principal contributor to permanent renal injury. Ligand-receptor pairing revealed critical intercellular crosstalk underpins damage-induced activation of immune cells. These results provide novel insight into the AAI-induced kidney injury and point out potential pathways for future therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%

Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy

Chen¹,

Luo²,

Wang³

et al. 2022

JCI Insight

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“…In lipopolysaccharide (LPS)-induced AKI models, angiopoietin-like protein 3 knockout mice showed alleviated ER stress and apoptosis via the inhibition of the ROS/GRP78/BAX pathway [ 25 ]. Forsythiaside A suppressed ER stress-induced inflammation and apoptosis, thereby suggesting a pivotal role of ER stress in sepsis-induced AKI [ 26 , 27 ]. GRP170, an ER protein regulating the degradation and assembly of the epithelial sodium channel, inhibits UPR and ER stress, which protects against ischemia- and sepsis-induced AKI [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis

Jin,

Yang,

Zhu

et al. 2024

Cell Death Dis

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Acute kidney injury (AKI) constitutes a prevalent clinical syndrome characterized by elevated morbidity and mortality rates, emerging as a significant public health issue. This study investigates the interplay between endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and ER-associated degradation (ER-phagy) in the pathogenesis of AKI. We employed four distinct murine models of AKI—induced by contrast media, ischemia–reperfusion injury, cisplatin, and folic acid—to elucidate the relationship between ER-phagy, ER stress, and apoptosis. Our findings reveal a marked decrease in ER-phagy coinciding with an accumulation of damaged ER, elevated ER stress, and increased apoptosis across all AKI models. Importantly, overexpression of DDRGK1 in HK-2 cells enhanced ER-phagy levels, ameliorating contrast-induced ER stress and apoptosis. These findings unveil a novel protective mechanism in AKI, wherein DDRGK1–UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Our results thereby contribute to understanding the molecular underpinnings of AKI and offer potential therapeutic targets for its treatment.

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“… 37 On the other hand, lipid peroxidation could up-regulate apoptosis through endoplasmic reticulum stress (ER stress) and induce apoptosis through TRAIL and FAS pathways. 38 , 39 Therefore, the ability to induce the production of ROS could be used as one of the indexes to judge the effectiveness of the sonosensitizer. In this work, we found that SDT mediated by IR-820@NBs could effectively induce the production of ROS and the change of mitochondrial membrane potential.…”

Section: Discussionmentioning

confidence: 99%

IR-820@NBs Combined with MG-132 Enhances the Anti-Hepatocellular Carcinoma Effect of Sonodynamic Therapy

Wang,

Tian

et al. 2023

IJN

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Purpose Sonodynamic therapy (SDT) is a promising and significant measure for the treatment of tumors. However, the internal situation of hepatocellular carcinoma (HCC) is complex, separate SDT treatment is difficult to play a good therapeutic effect. Here, we used SDT combined with MG-132 to mediate apoptosis and autophagy of HCC cells to achieve the purpose of treatment of cancer. Methods To determine the generated reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm), HepG2 cells were stained by 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) and 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) staining to determine the IR-820@NBs-mediated SDT to achieve HCC therapy through the mitochondrial pathway. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to detect cell viability and apoptosis rate of HepG2 cells. Autophagy was detected by mCherry-GFP-LC3B fluorescence labeling. Chloroquine (Cq) pretreatment was used to explore the relationship between autophagy and apoptosis. To detect the ability of HepG2 cells migration and invasion, cell scratch assay and transwell assay were used. Results The successfully prepared IR-820@NBs could effectively overcome the shortcomings of IR-820 and induce lethal levels of ROS by ultrasound irradiation. As a dual agonist of apoptosis and autophagy, MG-132 could effectively enhance the efficacy of SDT in the process of treating HCC. After pre-treatment with Cq, the cell activity increased and the level of apoptosis decreased, which proved that apoptosis and autophagy were induced by combined therapy, autophagy, and apoptosis have the synergistic anti-tumor effect, and part of apoptosis was autophagy-dependent. After combined therapy, the activity and invasive ability of HCC cells decreased significantly. Conclusion SDT combined with MG-132 in the process of treating liver cancer could effectively induce apoptosis and autophagy anti-tumor therapy, which is helpful to the research of new methods to treat liver cancer.

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TIMP2 mediates endoplasmic reticulum stress contributing to sepsis‐induced acute kidney injury

Cited by 17 publications

References 58 publications

Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy

Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis

IR-820@NBs Combined with MG-132 Enhances the Anti-Hepatocellular Carcinoma Effect of Sonodynamic Therapy

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