TY - JOUR
T1 - The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis
AU - Madaio, Michael P.
AU - Czikora, Istvan
AU - Kvirkvelia, Nino
AU - McMenamin, Malgorzata
AU - Yue, Qiang
AU - Liu, Ting
AU - Flores Toque, Haroldo Alfredo
AU - Sridhar, Supriya
AU - Covington, Katherine
AU - O'Connor, Paul M
AU - Caldwell, Robert William
AU - Chen, Jiankang
AU - Clauss, Matthias
AU - Brands, Michael W
AU - Eaton, Douglas C.
AU - Romero Lucas, Maritza Josefina
AU - Lucas, Rudolf
N1 - Funding Information:
This work was supported by grants R01 DK100564 (MPM, RL), DK110409 (DCE), DK099548 (POC), and DK114328 (J-KC) from the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases, as well as grants R01 HL138410 (RL), HL128207 (MWB), HL129843 (MC), and P01 HL134604 (MWB, POC) from the NIH/National Heart, Lung, and Blood Institute; grant 17GRNT33410653 (MJR) and AHA 17SDG33680024 Award (IC) from the AHA; Innovative Grant 1-INO-2017-459-A-N from the JDRF (MJR); and grant #1-16-IBS-196 from the ADA (RL). Part of these results were published as an abstract for International Kidney Week 2016.
Publisher Copyright:
© 2019 International Society of Nephrology
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
KW - cytokines
KW - endothelium
KW - glomerulus
KW - prostaglandins
KW - proteinuria
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U2 - 10.1016/j.kint.2018.12.022
DO - 10.1016/j.kint.2018.12.022
M3 - Article
C2 - 30905471
AN - SCOPUS:85065528377
SN - 0085-2538
VL - 95
SP - 1359
EP - 1372
JO - Kidney International
JF - Kidney International
IS - 6
ER -