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

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.