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Abstract: TH-PO889

Effect of DsbA-L on Renal Ectopic Fat Deposition and Lipid-Related Kidney Damage in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Chen, Xianghui, Second Xiangya Hospital Central South University, Changsha, China
  • Han, Yachun, Second Xiangya Hospital Central South University, Changsha, China
  • Yang, Ming, Second Xiangya Hospital Central South University, Changsha, China
  • Gao, Peng, Second Xiangya Hospital Central South University, Changsha, China
  • Kanwar, Yashpal S., Northwestern University Medical School, Chicago, Illinois, United States
  • Sun, Lin, Second Xiangya Hospital Central South University, Changsha, China
Background

Emerging evidence suggests that ectopic fat deposition (EFD) in the kidney is related to the progression of diabetic nephropathy (DN), but the mechanism remains elusive.Disulfide-bond A oxidoreductase-like protein (DsbA-L) also known as Glutathione S-transferase kappa 1 (GSTK1),which has been demonstrated to regulate adiponectin multimerization, alleviate endoplasmic reticulum stress and prevent obesity-induced inflammation and insulin resistance. But the role of DsbA-L in renal EFD and lipid-related kidney damage is unknown.

Methods

In this study, patients with DN, DsbA-L deficiency mice (DsbA-L-/- mice), DsbA-L overexpression mice and HK-2 cells, a human proximal tubular cells line were used. Differentially expressed genes were identified by transcriptome in the kidney tissues of mice. Oil red o staining , electron microscope and immunostaining of adipocyte differentiation-related protein (ADRP) were used to observe or detect the lipid depostion in the kidney tissues of DN patients or mice.

Results

Here, we identified decreased expression of disulfide - bond A oxidoreductase-like protein (DsbA-L) and increased expression of adipocyte differentiation-related protein (ADRP) in the kidney of diabetic mice. Further, obvious lipid droplets (LDs) deposition and decreased DsbA-L expression were observed in the kidney of diabetic mice, accompanied by abnormal levels of phosphorylation of 5’AMP-activated kinase (p-AMPK), p-adipose triglyceride lipase (p-ATGL), p-3-hydroxy-3-methylglutaryl- CoA reductase (p-HMGCR), collagen I and fibronectin (FN). The above alterations were further increased in diabetic DsbA-L-/- mice. Overexpression of DsbA-L ameliorated high glucose (HG)-induced intracellular LDs deposition, whereas DsbA-L siRNA treatment aggravated it and was accompanied by reduced levels of p-AMPK, p-ATGL and p-HMGCR in HK-2 cells, a human proximal tubular cells line. Additionally, HG plus palmitic acid (PA) enhanced the expression of interleukin-1β and interleukin-18, which was further increased after DsbA-L siRNA treatment, but was alleviated by cotreatment with an AMPK activator. In the kidneys of DN patients, LDs deposition was negatively associated with DsbA-L expression but positively correlated with kidney damage.

Conclusion


Collectively, DsbA-L protects against renal EFD and lipid-related kidney damage via AMPK pathway.

Funding

  • Other NIH Support