iScience (Dec 2024)

Tumor necrosis factor-stimulated gene-6 inhibits endoplasmic reticulum stress in the ischemic mouse kidney

  • Bo Lu,
  • Li Xing,
  • Xiang-Yang Zhu,
  • Hui Tang,
  • Brandon Lu,
  • Fei Yuan,
  • Yazan Almasry,
  • Alexander Krueger,
  • Samer H. Barsom,
  • James D. Krier,
  • Kyra L. Jordan,
  • Amir Lerman,
  • Alfonso Eirin,
  • Lilach O. Lerman

Journal volume & issue
Vol. 27, no. 12
p. 111454

Abstract

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Summary: Kidney tissue injury in renal artery stenosis (RAS) involves inflammation, endoplasmic reticulum stress (ERS), and mitochondria damage. Tumor necrosis factor-stimulated gene-6 (TSG-6), an endogenous reparative molecule, may decrease ERS and improve renal function. To assess its impact on the stenotic murine kidney, we injected TSG-6 or vehicle for two weeks in mice with RAS. At completion, we assessed stenotic kidney function and oxygenation, inflammation, and expression of ERS-related genes. TSG-6 treatment reduced renal hypoxia, urinary protein and plasma creatinine levels, renal fibrosis, and apoptosis. TSG-6 also exhibited an anti-inflammatory effect, reflected in the downregulated expression of the Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway in murine kidneys in vivo and HK-2 cells in vitro. Moreover, ERS-related molecules were downregulated after TSG-6 treatment, while most indicators of mitochondrial unfolded protein response remained unaltered. Therefore, TSG-6 alleviates inflammation, ERS, apoptosis, and fibrosis in the post-stenotic mouse kidney. These observations position TSG-6 as a potential therapeutic tool in RAS.

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