The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis

• Authors: Michael P. Madaio, Augusta University; Istvan Czikora, Augusta University; Nino Kvirkvelia, Augusta University; Malgorzata McMenamin, Augusta University; Qiang Yue, Emory University; Ting Liu, Augusta University; Haroldo Toque, Augusta University; Supriya Sridhar, Augusta University; Katherine Covington, Augusta University; Rabei Alaisami, Augusta University; Paul O'Connor, Augusta University; Robert W. Caldwell, Augusta University; Jian-Kang Chen, Augusta University; Matthias Claus, Indiana Center for Vascular Biology and Medicine; Michael W. Brands, Augusta University; Douglas Eaton, Emory University; Maritza Romero, Augusta University; Rudolf Lucas, Augusta University
• Journal Title: Kidney International
• Volume: Volume 95, Number 6
• Publisher: Elsevier Science Inc. | 2019-06-01, Pages 1359-1372
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.kint.2018.12.022
• Subjects: Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Urology & Nephrology; cytokines; endothelium; glomerulus; prostaglandins; proteinuria; Tumor necrosis factor; Nitric oxide synthase; Renal injury; Protein kinase C; Factor alpha; ENAC; P38; Glomerulonephritis; Contributes; Receptors

Abstract

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 (GECs) 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 E2 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.