Disulfide-bond A oxidoreductase-like protein protects against ectopic fat deposition and lipid-related kidney damage in diabetic nephropathy

Xianghui Chen, Yachun Han, Peng Gao, Ming Yang, Li Xiao, Xiaofen Xiong, Hao Zhao, Chengyuan Tang, Guochun Chen, Xuejing Zhu, Shuguang Yuan, Fuyou Liu, Lily Q. Dong, Feng Liu, Yashpal S. Kanwar, Lin Sun

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Ectopic fat deposition (EFD) in the kidney has been shown to play a causal role in diabetic nephropathy; however, the mechanism underlying EFD remains elusive. By transcriptome analysis, we found decreased expression levels of disulfide-bond A oxidoreductase-like protein (DsbA-L) in the kidneys of diabetic mice (induced by high-fat diet plus Streptozotocin) compared with control mice. Increased expression of adipocyte differentiation–related protein and abnormal levels of collagen I, fibronectin, and phosphorylated 5′AMP-activated kinase (p-AMPK), adipose triglyceride lipase (p-ATGL), and HMG-CoA reductase (p-HMGCR) were also observed in diabetic mice. These alterations were accompanied by deposition of lipid droplets in the kidney, and were more pronounced in diabetic DsbA-L knockout mice. In vitro, overexpression of DsbA-L ameliorated high glucose–induced intracellular lipid droplet deposition in a human proximal tubular cell line, and DsbA-L siRNA aggravated lipid droplet deposition and reduced the levels of p-AMPK, p-ATGL, and p-HMGCR. High glucose and palmitic acid treatment enhanced the expression of interleukin-1β and interleukin-18; these enhancements were further increased after treatment with DsbA-L siRNA but alleviated by co-treatment with an AMPK activator. In kidney biopsy tissue from patients with diabetic nephropathy, DsbA-L expression was negatively correlated with EFD and tubular damage. Collectively, these results suggest that DsbA-L has a protective role against EFD and lipid-related kidney damage in diabetic nephropathy. Activation of the AMPK pathway is a potential mechanism underlying DsbA-L action in the kidney.

Original languageEnglish (US)
Pages (from-to)880-895
Number of pages16
JournalKidney international
Volume95
Issue number4
DOIs
StatePublished - Apr 2019

Keywords

  • diabetic nephropathy
  • disulfide-bond A oxidoreductase-like protein
  • ectopic fat deposition

ASJC Scopus subject areas

  • Nephrology

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