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
Affiliations
Bo Lu
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Shanghai 200437, China
Li Xing
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu Province, China
Xiang-Yang Zhu
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Hui Tang
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Brandon Lu
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Fei Yuan
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Urology, National Children’s Medical Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yazan Almasry
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Alexander Krueger
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Samer H. Barsom
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
James D. Krier
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Kyra L. Jordan
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Amir Lerman
Department of Cardiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Alfonso Eirin
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Lilach O. Lerman
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Corresponding author
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.
