DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrityResearch in context
Background: The mitochondrial associated endoplasmic reticulum (ER) membrane (MAM) provides a platform for communication between the mitochondria and ER, and it plays a vital role in many biological functions. Disulphide-bond A oxidoreductase-like protein (DsbA-L), expressed in the MAM, serves as an...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-05-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239641930283X |
| _version_ | 1818292450199863296 |
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| author | Ming Yang Li Zhao Peng Gao Xuejing Zhu Yachun Han Xianghui Chen Li Li Ying Xiao Ling Wei Chenrui Li Li Xiao Shuguang Yuan Fuyou Liu Lily Q. Dong Yashpal S. Kanwar Lin Sun |
| author_facet | Ming Yang Li Zhao Peng Gao Xuejing Zhu Yachun Han Xianghui Chen Li Li Ying Xiao Ling Wei Chenrui Li Li Xiao Shuguang Yuan Fuyou Liu Lily Q. Dong Yashpal S. Kanwar Lin Sun |
| author_sort | Ming Yang |
| collection | DOAJ |
| description | Background: The mitochondrial associated endoplasmic reticulum (ER) membrane (MAM) provides a platform for communication between the mitochondria and ER, and it plays a vital role in many biological functions. Disulphide-bond A oxidoreductase-like protein (DsbA-L), expressed in the MAM, serves as an antioxidant and reduces ER stress. However, the role of DsbA-L and MAM in kidney pathobiology remains unclear. Methods: Molecular biology techniques, transmission electron microscopy (TEM), in situ proximity ligation assays (PLAs), confocal microscopy, TUNEL staining and flow cytometry were utilized to analyse apoptosis and status of MAM in DsbA-L mutant mice. Findings: We showed that MAM was significantly reduced in the kidneys of streptozotocin-induced diabetic mice, which correlated with the extent of renal injury. We also observed a correlation between the loss of MAM integrity and increased apoptosis and renal injury in diabetic nephropathy (DN). These alterations were further exacerbated in diabetic DsbA-L gene-deficient mice (DsbA-L−/−). In vitro, overexpression of DsbA-L in HK-2 cells restored MAM integrity and reduced apoptosis induced by high-glucose ambience. These beneficial effects were partially blocked by overexpression of FATE-1, a MAM uncoupling protein. Finally, the expression of DsbA-L was positively correlated with MAM integrity in the kidneys of DN patients but negatively correlated with apoptosis and renal injury. Interpretation: Our results indicate that DsbA-L exerts an antiapoptotic effect by maintaining MAM integrity, which is apparently disrupted in DN. Fund: This work was supported by the National Natural Science Foundation of China (81730018), the National Key R&D Program of China (2016YFC1305501) and NIH (DK60635). Keywords: DsbA-L, Mitochondrial associated endoplasmic reticulum membrane (MAM), Apoptosis, Diabetic nephropathy, Tubulointerstitial injury |
| first_indexed | 2024-12-13T03:00:09Z |
| format | Article |
| id | doaj.art-34ed43cd4adf461fbfb54a7b2a40b900 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-13T03:00:09Z |
| publishDate | 2019-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-34ed43cd4adf461fbfb54a7b2a40b9002022-12-22T00:01:50ZengElsevierEBioMedicine2352-39642019-05-0143607619DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrityResearch in contextMing Yang0Li Zhao1Peng Gao2Xuejing Zhu3Yachun Han4Xianghui Chen5Li Li6Ying Xiao7Ling Wei8Chenrui Li9Li Xiao10Shuguang Yuan11Fuyou Liu12Lily Q. Dong13Yashpal S. Kanwar14Lin Sun15Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, ChinaDepartment of Cell Systems & Anatomy, University of Texas Health at San Antonio, San Antonio, TX 78229, USADepartments of Pathology & Medicine, Northwestern University, Chicago, IL, USADepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Corresponding author at: Department of Nephrology, The Second Xiangya Hospital, Hunan Key Laboratory of Kidney Disease and Blood Purification, Central South University, No. 139 Renmin Middle Road, Changsha, Hunan 410011, China.Background: The mitochondrial associated endoplasmic reticulum (ER) membrane (MAM) provides a platform for communication between the mitochondria and ER, and it plays a vital role in many biological functions. Disulphide-bond A oxidoreductase-like protein (DsbA-L), expressed in the MAM, serves as an antioxidant and reduces ER stress. However, the role of DsbA-L and MAM in kidney pathobiology remains unclear. Methods: Molecular biology techniques, transmission electron microscopy (TEM), in situ proximity ligation assays (PLAs), confocal microscopy, TUNEL staining and flow cytometry were utilized to analyse apoptosis and status of MAM in DsbA-L mutant mice. Findings: We showed that MAM was significantly reduced in the kidneys of streptozotocin-induced diabetic mice, which correlated with the extent of renal injury. We also observed a correlation between the loss of MAM integrity and increased apoptosis and renal injury in diabetic nephropathy (DN). These alterations were further exacerbated in diabetic DsbA-L gene-deficient mice (DsbA-L−/−). In vitro, overexpression of DsbA-L in HK-2 cells restored MAM integrity and reduced apoptosis induced by high-glucose ambience. These beneficial effects were partially blocked by overexpression of FATE-1, a MAM uncoupling protein. Finally, the expression of DsbA-L was positively correlated with MAM integrity in the kidneys of DN patients but negatively correlated with apoptosis and renal injury. Interpretation: Our results indicate that DsbA-L exerts an antiapoptotic effect by maintaining MAM integrity, which is apparently disrupted in DN. Fund: This work was supported by the National Natural Science Foundation of China (81730018), the National Key R&D Program of China (2016YFC1305501) and NIH (DK60635). Keywords: DsbA-L, Mitochondrial associated endoplasmic reticulum membrane (MAM), Apoptosis, Diabetic nephropathy, Tubulointerstitial injuryhttp://www.sciencedirect.com/science/article/pii/S235239641930283X |
| spellingShingle | Ming Yang Li Zhao Peng Gao Xuejing Zhu Yachun Han Xianghui Chen Li Li Ying Xiao Ling Wei Chenrui Li Li Xiao Shuguang Yuan Fuyou Liu Lily Q. Dong Yashpal S. Kanwar Lin Sun DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrityResearch in context EBioMedicine |
| title | DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrityResearch in context |
| title_full | DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrityResearch in context |
| title_fullStr | DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrityResearch in context |
| title_full_unstemmed | DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrityResearch in context |
| title_short | DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrityResearch in context |
| title_sort | dsba l ameliorates high glucose induced tubular damage through maintaining mam integrityresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S235239641930283X |
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