The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis
| Autor: | Michael W. Brands, Douglas C. Eaton, Maritza J. Romero, Ting Liu, Rudolf Lucas, Qiang Yue, Robert W. Caldwell, Nino Kvirkvelia, Paul M. O'Connor, Jian-Kang Chen, Malgorzata McMenamin, Matthias Clauss, Supriya Sridhar, Istvan Czikora, Katherine Covington, Rabei Alaisami, Michael P. Madaio, Haroldo A. Toque |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Epithelial sodium channel Patch-Clamp Techniques Endothelium Kidney Glomerulus Primary Cell Culture 030232 urology & nephrology Inflammation Lung injury Pharmacology Nitric Oxide Peptides Cyclic Dinoprostone Article Blood Urea Nitrogen Cell Line Nitric oxide Mice 03 medical and health sciences chemistry.chemical_compound Glomerulonephritis 0302 clinical medicine medicine Animals Humans Epithelial Sodium Channels Receptor Tumor Necrosis Factor-alpha Chemistry Endothelial Cells medicine.disease Disease Models Animal Proteinuria 030104 developmental biology medicine.anatomical_structure Nephrology Th17 Cells Female Tumor necrosis factor alpha medicine.symptom Injections Intraperitoneal Signal Transduction |
| Zdroj: | Kidney Int |
| ISSN: | 0085-2538 |
| Popis: | In mice, the initial stage of nephrotoxic serum-induced nephritis (NTN) mimics antibody-mediated human glomerulonephritis. Local immune deposits generate tumor necrosis factor (TNF), which activates pro-inflammatory pathways in glomerular endothelial cells (GEC) and podocytes. Because TNF receptors mediate antibacterial defense, existing anti-TNF therapies can promote infection; however, we have previously demonstrated that different functional domains of TNF may have opposing effects. The TIP peptide mimics the lectin-like domain of TNF, and has been shown to blunt inflammation in acute lung injury without impairing TNF receptor-mediated antibacterial activity. We evaluated the impact of TIP peptide in NTN. Intraperitoneal administration of TIP peptide reduced inflammation, proteinuria, and blood urea nitrogen. The protective effect was blocked by the cyclooxygenase inhibitor indomethacin, indicating involvement of prostaglandins. Targeted glomerular delivery of TIP peptide improved pathology in moderate NTN and reduced mortality in severe NTN, indicating a local protective effect. We show that TIP peptide activates the epithelial sodium channel (ENaC), which is expressed by GEC, upon binding to the channel’s α subunit. In vitro, TNF treatment of GEC activated pro-inflammatory pathways and decreased the generation of prostaglandin E(2) and nitric oxide, which promote recovery from NTN. TIP peptide counteracted these effects. Despite the capacity of TIP peptide to activate ENaC, it did not increase mean arterial blood pressure in mice. In the later autologous phase of NTN, TIP peptide blunted the infiltration of Th17 cells. By countering the deleterious effects of TNF through direct actions in GEC, TIP peptide could provide a novel strategy to treat glomerular inflammation. |
| Databáze: | OpenAIRE |
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