Journal
FASEB JOURNAL
Volume 36, Issue 4, Pages -Publisher
WILEY
DOI: 10.1096/fj.202101555RR
Keywords
acute kidney injury (AKI); apoptosis; endoplasmic reticulum stress (ER stress); sepsis; tissue inhibitor of metalloproteinase 2 (TIMP2)
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Funding
- National Natural Science Foundation of China (NSFC) [81772046, 81971816, 82102298]
- Major National Science and Technology Projects of China [2020ZX09201007]
- Innovation Cultivation Foundation of Wuhan University/Zhongnan Hospital [413000345/CXPY2020017]
- Research Project Foundation of Zhongnan Hospital [ZNYB2020013]
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This study highlights the significance of TIMP2 in septic AKI, showing that it can attenuate ER stress-mediated apoptosis and mitigate renal injury.
Tissue inhibitor of metalloproteinase 2 (TIMP2) has been recognized as an important biomarker for predicting acute kidney injury (AKI) because of its involvement in the process of inflammation and apoptosis in septic AKI. Endoplasmic reticulum (ER) stress, a condition of disrupted ER homeostasis, is implicated in multiple pathophysiological processes, including kidney disease. Herein, we investigated the correlation between ER stress and septic AKI and further explored how TIMP2 regulated ER stress-mediated apoptosis. To assess the role of TIMP2 in sepsis-induced AKI, we used a cecal ligation and puncture (CLP) model in mice with tubule-specific deficiency of TIMP2 (Ksp-Cre/TIMP2(flox)(/)(flox)) and their wild-type counterparts. Compared to the wild-type mice, TIMP2-deficient mice demonstrated lower serum creatinine levels and decreased ER stress-mediated apoptosis when subjected to CLP. Interestingly, in human kidney (HK-2) cells, overexpression of TIMP2 caused ER stress, whereas TIMP2 knockdown attenuated lipopolysaccharide-induced ER stress and apoptosis. TIMP2 interacted with the binding immunoglobulin protein, an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress. This study identified that the deletion of TIMP2 in mouse tubules mitigated sepsis-induced AKI by inhibiting ER stress-mediated apoptosis, which might be a potential therapeutic strategy to alleviate renal injury.
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