Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1
Abstract Podocyte injury and loss are critical events in diabetic nephropathy (DN); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that asparaginyl endopeptidase (AEP) protects against podocyte injury through modulating the dynamics of the cytoskeleton. AEP was hig...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04621-2 |
| _version_ | 1818501027247161344 |
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| author | Chuntao Lei Mengran Li Yang Qiu Yaru Xie Zhe Hao Xingjie Yin Zhentao Zhang Hua Su Linlin Yang Jihong Lin Hans-Peter Hammes Chun Zhang |
| author_facet | Chuntao Lei Mengran Li Yang Qiu Yaru Xie Zhe Hao Xingjie Yin Zhentao Zhang Hua Su Linlin Yang Jihong Lin Hans-Peter Hammes Chun Zhang |
| author_sort | Chuntao Lei |
| collection | DOAJ |
| description | Abstract Podocyte injury and loss are critical events in diabetic nephropathy (DN); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that asparaginyl endopeptidase (AEP) protects against podocyte injury through modulating the dynamics of the cytoskeleton. AEP was highly upregulated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes; however, AEP gene knockout and its compound inhibitor treatment accelerated DN in streptozotocin-induced diabetic mice, whereas specific induction of AEP in glomerular cells attenuated podocyte injury and renal function deterioration. In vitro, elevated AEP was involved in actin cytoskeleton maintenance and anti-apoptosis effects. Mechanistically, we found that AEP directly cleaved the actin-binding protein cofilin-1 after the asparagine 138 (N138) site. The protein levels of endogenous cofilin-1 1-138 fragments were upregulated in diabetic podocytes, consistent with the changes in AEP levels. Importantly, we found that cofilin-1 1-138 fragments were remarkably unphosphorylated than full-length cofilin-1, indicating the enhanced cytoskeleton maintenance activity of cofilin-1 1-138. Then we validated cofilin-1 1-138 could rescue podocytes from cytoskeleton disarrangement and injury in diabetic conditions. Taken together, our data suggest a protective role of elevated AEP in podocyte injury during DN progression through cleaving cofilin-1 to maintain podocyte cytoskeleton dynamics and defend damage. |
| first_indexed | 2024-12-10T20:50:36Z |
| format | Article |
| id | doaj.art-ed967e4b788c4a10ab2ab1de097d6371 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-10T20:50:36Z |
| publishDate | 2022-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-ed967e4b788c4a10ab2ab1de097d63712022-12-22T01:34:06ZengNature Publishing GroupCell Death and Disease2041-48892022-02-0113211410.1038/s41419-022-04621-2Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1Chuntao Lei0Mengran Li1Yang Qiu2Yaru Xie3Zhe Hao4Xingjie Yin5Zhentao Zhang6Hua Su7Linlin Yang8Jihong Lin9Hans-Peter Hammes10Chun Zhang11Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Renmin Hospital of Wuhan UniversityDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology5th Medical Department, Medical Faculty Mannheim, Heidelberg University5th Medical Department, Medical Faculty Mannheim, Heidelberg University5th Medical Department, Medical Faculty Mannheim, Heidelberg UniversityDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Podocyte injury and loss are critical events in diabetic nephropathy (DN); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that asparaginyl endopeptidase (AEP) protects against podocyte injury through modulating the dynamics of the cytoskeleton. AEP was highly upregulated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes; however, AEP gene knockout and its compound inhibitor treatment accelerated DN in streptozotocin-induced diabetic mice, whereas specific induction of AEP in glomerular cells attenuated podocyte injury and renal function deterioration. In vitro, elevated AEP was involved in actin cytoskeleton maintenance and anti-apoptosis effects. Mechanistically, we found that AEP directly cleaved the actin-binding protein cofilin-1 after the asparagine 138 (N138) site. The protein levels of endogenous cofilin-1 1-138 fragments were upregulated in diabetic podocytes, consistent with the changes in AEP levels. Importantly, we found that cofilin-1 1-138 fragments were remarkably unphosphorylated than full-length cofilin-1, indicating the enhanced cytoskeleton maintenance activity of cofilin-1 1-138. Then we validated cofilin-1 1-138 could rescue podocytes from cytoskeleton disarrangement and injury in diabetic conditions. Taken together, our data suggest a protective role of elevated AEP in podocyte injury during DN progression through cleaving cofilin-1 to maintain podocyte cytoskeleton dynamics and defend damage.https://doi.org/10.1038/s41419-022-04621-2 |
| spellingShingle | Chuntao Lei Mengran Li Yang Qiu Yaru Xie Zhe Hao Xingjie Yin Zhentao Zhang Hua Su Linlin Yang Jihong Lin Hans-Peter Hammes Chun Zhang Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1 Cell Death and Disease |
| title | Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1 |
| title_full | Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1 |
| title_fullStr | Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1 |
| title_full_unstemmed | Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1 |
| title_short | Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1 |
| title_sort | asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin 1 |
| url | https://doi.org/10.1038/s41419-022-04621-2 |
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