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DsbA-L Ameliorates Glucose-Induced Tubular Damage Through Maintaining MAM Integrity

39 Pages Posted: 8 Mar 2019

See all articles by Ming Yang

Ming Yang

Central South University - Department of Nephrology

Li Zhao

Central South University - Department of Nephrology

Peng Gao

Central South University - Department of Nephrology

Xuejing Zhu

Central South University - Department of Nephrology

Yachun Han

Central South University - Department of Nephrology

Xianghui Chen

Central South University - Department of Nephrology

Li Li

Central South University - Department of Nephrology

Ying Xiao

Central South University - Department of Nephrology

Ling Wei

Central South University - Department of Nephrology

Li Xiao

Central South University - Department of Nephrology

Shuguang Yuan

Central South University - Department of Nephrology

Fuyou Liu

Central South University - Department of Nephrology

Lily Q. Dong

University of Texas at San Antonio - Department of Cell Systems and Anatomy

Yashpal S. Kanwar

Northwestern University - Department of Medicine

Lin Sun

Central South University - Department of Nephrology

More...

Abstract

Mitochondrial associated endoplasmic reticulum (ER) membrane (MAM) provides a platform for communication between mitochondria and ER, and it plays a vital role in multitude of biological functions. Disulfide-bond A oxidoreductase-like protein (DsbA-L), expressed in the MAM, serves as an antioxidant and reduces the ER stress. However, the role of DsbA-L and MAM in kidney pathobiology remains enigmatic. Here, we show that MAM was significantly reduced in the kidneys of streptozocin-induced diabetic mice, which correlated with the extent of renal injury. We also observed that there was a correlation between the loss of MAM integrity/expression and increased apoptosis and renal injury in DN. Such alterations were further exacerbated in diabetic DsbA-L gene-deficient mice (DsbA-L-/-). In vitro, overexpression of DsbA-L in HK-2 cells restored the MAM integrity/expression and reduced apoptosis induced by high glucose ambience.These beneficial effects were partially blocked by overexpression of FATE-1, an MAM uncoupling protein. Finally, the expression of DsbA-L positively correlated with MAM integrity in the kidney of DN patients, but were negatively correlated with apoptosis and renal injury. These results indicate that DsbA-L exerts an anti-apoptotic effect by maintaining the MAM integrity or inter-organelle (ER and mitochondria) spatial organization, which apparently gets disrupted in DN.

Funding Statement: This work was funded by the National Natural Science Foundation of China (81730018) and National Key R&D Program of China (2016YFC1305500).

Declaration of Interests: Dr. Sun has nothing to disclose. All other authors have nothing to disclose.

Ethics Approval Statement: All animal experiments were performed in accordance with the regulations established by the Institutional Committee for Care and Use of Laboratory Animals at the Central South University, China.

Keywords: DsbA-L; Mitochondrial associated endoplasmic reticulum membrane (MAM); Apoptosis; Diabetic nephropathy; Tubulo-interstitial injury

Suggested Citation

Yang, Ming and Zhao, Li and Gao, Peng and Zhu, Xuejing and Han, Yachun and Chen, Xianghui and Li, Li and Xiao, Ying and Wei, Ling and Xiao, Li and Yuan, Shuguang and Liu, Fuyou and Dong, Lily Q. and Kanwar, Yashpal S. and Sun, Lin, DsbA-L Ameliorates Glucose-Induced Tubular Damage Through Maintaining MAM Integrity (January 12, 2019). Available at SSRN: https://ssrn.com/abstract=3314419

Ming Yang

Central South University - Department of Nephrology ( email )

Hunan, 410011
China

Li Zhao

Central South University - Department of Nephrology

Hunan, 410011
China

Peng Gao

Central South University - Department of Nephrology

Hunan, 410011
China

Xuejing Zhu

Central South University - Department of Nephrology ( email )

Hunan, 410011
China

Yachun Han

Central South University - Department of Nephrology ( email )

Hunan, 410011
China

Xianghui Chen

Central South University - Department of Nephrology

Hunan, 410011
China

Li Li

Central South University - Department of Nephrology

Hunan, 410011
China

Ying Xiao

Central South University - Department of Nephrology ( email )

Hunan, 410011
China

Ling Wei

Central South University - Department of Nephrology ( email )

Hunan, 410011
China

Li Xiao

Central South University - Department of Nephrology

Hunan, 410011
China

Shuguang Yuan

Central South University - Department of Nephrology

Hunan, 410011
China

Fuyou Liu

Central South University - Department of Nephrology

Hunan, 410011
China

Lily Q. Dong

University of Texas at San Antonio - Department of Cell Systems and Anatomy

One UTSA Circle
San Antonio, TX 78249
United States

Yashpal S. Kanwar

Northwestern University - Department of Medicine

United States

Lin Sun (Contact Author)

Central South University - Department of Nephrology ( email )

Hunan, 410011
China

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