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Kidney Int. 2019 Jun;95(6):1359-1372. doi: 10.1016/j.kint.2018.12.022. Epub 2019 Mar 21.

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

Author information

1
Department of Medicine, Augusta University, Augusta, Georgia, USA. Electronic address: MMADAIO@augusta.edu.
2
Vascular Biology Center, Augusta University, Augusta, Georgia, USA; Department of Physiology, Augusta University, Augusta, Georgia, USA.
3
Department of Medicine, Augusta University, Augusta, Georgia, USA.
4
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
5
Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, USA.
6
Vascular Biology Center, Augusta University, Augusta, Georgia, USA.
7
Department of Physiology, Augusta University, Augusta, Georgia, USA.
8
Department of Pharmacology and Toxicology, Augusta University, Augusta, Georgia, USA.
9
Indiana Center for Vascular Biology and Medicine, RLR-VA Medical Center, Indianapolis, Indiana, USA.
10
Vascular Biology Center, Augusta University, Augusta, Georgia, USA; Department of Pharmacology and Toxicology, Augusta University, Augusta, Georgia, USA; Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
11
Department of Medicine, Augusta University, Augusta, Georgia, USA; Vascular Biology Center, Augusta University, Augusta, Georgia, USA; Department of Pharmacology and Toxicology, Augusta University, Augusta, Georgia, USA. Electronic address: rlucas@augusta.edu.

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.

KEYWORDS:

cytokines; endothelium; glomerulus; prostaglandins; proteinuria

PMID:
30905471
PMCID:
PMC6534471
[Available on 2020-06-01]
DOI:
10.1016/j.kint.2018.12.022

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