Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury
Backgroud: Ferroptosis is a form of regulated cell death in ischemia-reperfusion (I/R) injury models. Acute kidney injury (AKI) induced by I/R injury can result in cell death, and subcellular structural changes, including expansion of the endoplasmic reticulum (ER), mitochondrial shrinkage, and othe...
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Frontiers Media S.A.
2022-08-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.927641/full |
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| author | Yan Liang Yan Liang Yan Liang Zhenjie Liu Zhenjie Liu Lingyun Qu Lingyun Qu Yingzi Wang Yali Zhou Lulu Liang Lulu Liang Lulu Liang Yanhong Guo Lin Tang Lin Tang |
| author_facet | Yan Liang Yan Liang Yan Liang Zhenjie Liu Zhenjie Liu Lingyun Qu Lingyun Qu Yingzi Wang Yali Zhou Lulu Liang Lulu Liang Lulu Liang Yanhong Guo Lin Tang Lin Tang |
| author_sort | Yan Liang |
| collection | DOAJ |
| description | Backgroud: Ferroptosis is a form of regulated cell death in ischemia-reperfusion (I/R) injury models. Acute kidney injury (AKI) induced by I/R injury can result in cell death, and subcellular structural changes, including expansion of the endoplasmic reticulum (ER), mitochondrial shrinkage, and other morphological changes. Inositol requiring enzyme 1 (IRE1) a proximal ER stress sensor, activates c-Jun NH2-terminal kinases (JNK) in response to ER stress, which is inextricably linked to ER.Method: To determine the resulting damage and relationship between ferroptosis and the IRE1/JNK pathway in AKI, we modeled AKI in I/R renal injury mice and hypoxia/reoxygenation (H/R) HK-2 cells, as in vivo and in vitro experiments, respectively.Results: In I/R renal injury mice, we found that abnormal renal function; damage of renal tubular epithelial cells; activation of the IRE1/JNK pathway and ferroptosis. Our in vitro study showed a large number of reactive oxygen species and more ferroptotic mitochondria in H/R HK-2 cells. By inhibiting IRE1/JNK in I/R renal injury mice, we observed decreased blood urea nitrogen, creatinine, and tissue injury, compared with the I/R group, we also found the markers of ferroptosis changed, including decreased 4-hydroxynonenal and increased glutathione peroxidase 4, as well as in H/R induced IRE1/JNK knock-down HK-2 cell lines (stable depletion). Furthermore, inhibition of ferroptosis could also attenuate the IRE1/JNK pathway in mice following I/R and HK-2 cells following H/R.Conclusion: We observed cross-talk between the IRE1/JNK pathway and ferroptosis in I/R or H/R induced AKI. Our findings suggest that ferroptosis plays an important role in I/R induced AKI, and that inhibition of the IRE1/JNK pathway can protect against I/R induced renal injury by inhibiting ferroptosis. The inhibition of the IRE1/JNK pathway could therefore be a feasible therapeutic target for treatment of AKI. |
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| language | English |
| last_indexed | 2024-12-10T19:30:38Z |
| publishDate | 2022-08-01 |
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| spelling | doaj.art-d0a3ebab6fe04ccebda38df26524cd232022-12-22T01:36:16ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-08-011310.3389/fphar.2022.927641927641Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injuryYan Liang0Yan Liang1Yan Liang2Zhenjie Liu3Zhenjie Liu4Lingyun Qu5Lingyun Qu6Yingzi Wang7Yali Zhou8Lulu Liang9Lulu Liang10Lulu Liang11Yanhong Guo12Lin Tang13Lin Tang14Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaResearch Institute of Nephrology, Zhengzhou University, Zhengzhou, ChinaKey Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, ChinaDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaResearch Institute of Nephrology, Zhengzhou University, Zhengzhou, ChinaDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaResearch Institute of Nephrology, Zhengzhou University, Zhengzhou, ChinaDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaResearch Institute of Nephrology, Zhengzhou University, Zhengzhou, ChinaKey Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, ChinaDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaResearch Institute of Nephrology, Zhengzhou University, Zhengzhou, ChinaBackgroud: Ferroptosis is a form of regulated cell death in ischemia-reperfusion (I/R) injury models. Acute kidney injury (AKI) induced by I/R injury can result in cell death, and subcellular structural changes, including expansion of the endoplasmic reticulum (ER), mitochondrial shrinkage, and other morphological changes. Inositol requiring enzyme 1 (IRE1) a proximal ER stress sensor, activates c-Jun NH2-terminal kinases (JNK) in response to ER stress, which is inextricably linked to ER.Method: To determine the resulting damage and relationship between ferroptosis and the IRE1/JNK pathway in AKI, we modeled AKI in I/R renal injury mice and hypoxia/reoxygenation (H/R) HK-2 cells, as in vivo and in vitro experiments, respectively.Results: In I/R renal injury mice, we found that abnormal renal function; damage of renal tubular epithelial cells; activation of the IRE1/JNK pathway and ferroptosis. Our in vitro study showed a large number of reactive oxygen species and more ferroptotic mitochondria in H/R HK-2 cells. By inhibiting IRE1/JNK in I/R renal injury mice, we observed decreased blood urea nitrogen, creatinine, and tissue injury, compared with the I/R group, we also found the markers of ferroptosis changed, including decreased 4-hydroxynonenal and increased glutathione peroxidase 4, as well as in H/R induced IRE1/JNK knock-down HK-2 cell lines (stable depletion). Furthermore, inhibition of ferroptosis could also attenuate the IRE1/JNK pathway in mice following I/R and HK-2 cells following H/R.Conclusion: We observed cross-talk between the IRE1/JNK pathway and ferroptosis in I/R or H/R induced AKI. Our findings suggest that ferroptosis plays an important role in I/R induced AKI, and that inhibition of the IRE1/JNK pathway can protect against I/R induced renal injury by inhibiting ferroptosis. The inhibition of the IRE1/JNK pathway could therefore be a feasible therapeutic target for treatment of AKI.https://www.frontiersin.org/articles/10.3389/fphar.2022.927641/fullAKI (acute kidney injury)IRE1 (inositol-requiring enzyme 1)JNK (c-Jun N-terminal kinase)ferroptosisER stresstubular epithelial cells |
| spellingShingle | Yan Liang Yan Liang Yan Liang Zhenjie Liu Zhenjie Liu Lingyun Qu Lingyun Qu Yingzi Wang Yali Zhou Lulu Liang Lulu Liang Lulu Liang Yanhong Guo Lin Tang Lin Tang Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury Frontiers in Pharmacology AKI (acute kidney injury) IRE1 (inositol-requiring enzyme 1) JNK (c-Jun N-terminal kinase) ferroptosis ER stress tubular epithelial cells |
| title | Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury |
| title_full | Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury |
| title_fullStr | Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury |
| title_full_unstemmed | Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury |
| title_short | Inhibition of the IRE1/JNK pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury |
| title_sort | inhibition of the ire1 jnk pathway in renal tubular epithelial cells attenuates ferroptosis in acute kidney injury |
| topic | AKI (acute kidney injury) IRE1 (inositol-requiring enzyme 1) JNK (c-Jun N-terminal kinase) ferroptosis ER stress tubular epithelial cells |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.927641/full |
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