DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrity

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

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Abstract

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).

Original languageEnglish (US)
Pages (from-to)607-619
Number of pages13
JournalEBioMedicine
Volume43
DOIs
StatePublished - May 2019

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Keywords

  • Apoptosis
  • Diabetic nephropathy
  • DsbA-L
  • Mitochondrial associated endoplasmic reticulum membrane (MAM)
  • Tubulointerstitial injury

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yang, M., Zhao, L., Gao, P., Zhu, X., Han, Y., Chen, X., Li, L., Xiao, Y., Wei, L., Li, C., Xiao, L., Yuan, S., Liu, F., Dong, L. Q., Kanwar, Y. S., & Sun, L. (2019). DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrity. EBioMedicine, 43, 607-619. https://doi.org/10.1016/j.ebiom.2019.04.044