Dihydroartemisinin ameliorates sepsis-induced hyperpermeability of glomerular endothelium via up-regulation of occludin expression

Biomed Pharmacother. 2018 Mar:99:313-318. doi: 10.1016/j.biopha.2018.01.078.

Abstract

Sepsis, the systemic inflammatory responses after infection, remains a serious cause of morbidity and mortality in critically ill patients. The anti-malarial agent dihydroartemisinin (DHA) has been shown to be anti-inflammatory. In this study, we examined the effects of DHA on sepsis-induced acute kidney injury (AKI) and explored the mechanism underlying its mode of action in AKI. In a lipopolysaccharide (LPS)-induced mouse model, we observed that DHA treatment ameliorated glomerular injury, and relieved elevation of the urine albumin to creatinine ratio (UACR) and serum creatinine. At a concentration of 25 μM, DHA had no effect on overall cellular viability or apoptosis in assays with human renal glomerular endothelial cells (HRGECs), but significantly inhibited the tumor necrosis factor-α (TNF-α)-induced hyperpermeability of HRGEC monolayers. We found that TNF-α decreases the expression of the junctional protein occludin in HRGECs, which is reversed by DHA. Taken together, our results demonstrate that DHA decreases permeability of the glomerular endothelium by maintenance of occludin expression. This suggests DHA may have therapeutic utility in sepsis-induced AKI.

Keywords: Dihydroartemisinin; Glomerular endothelial cells; Occludin; Permeability; Sepsis.

MeSH terms

  • Acute Kidney Injury / drug therapy
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology
  • Animals
  • Apoptosis / drug effects
  • Artemisinins / pharmacology
  • Artemisinins / therapeutic use*
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Endothelium / drug effects
  • Endothelium / pathology*
  • Humans
  • Kidney Glomerulus / pathology*
  • Lipopolysaccharides
  • Mice, Inbred C57BL
  • Occludin / metabolism*
  • Permeability
  • Sepsis / drug therapy*
  • Sepsis / metabolism*
  • Sepsis / pathology
  • Tumor Necrosis Factor-alpha
  • Up-Regulation* / drug effects

Substances

  • Artemisinins
  • Lipopolysaccharides
  • Occludin
  • Tumor Necrosis Factor-alpha
  • artenimol