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

Michael P. Madaio, Istvan Czikora, Nino Kvirkvelia, Malgorzata McMenamin, Qiang Yue, Ting Liu, Haroldo Alfredo Flores Toque, Supriya Sridhar, Katherine Covington, Rabei Alaisami, Paul M O'Connor, Robert William Caldwell, Jiankang Chen, Matthias Clauss, Michael W Brands, Douglas C. Eaton, Maritza Josefina Romero Lucas, Rudolf Lucas

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1359-1372
Number of pages14
JournalKidney International
Volume95
Issue number6
DOIs
StatePublished - Jun 1 2019

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Epithelial Sodium Channels
Nephritis
Tumor Necrosis Factor-alpha
Peptides
Serum
Endothelial Cells
Tumor Necrosis Factor Receptors
Inflammation
Arterial Pressure
Th17 Cells
Podocytes
Cyclooxygenase Inhibitors
Acute Lung Injury
Blood Urea Nitrogen
Glomerulonephritis
Proteinuria
Dinoprostone
Lectins
Indomethacin
Prostaglandins

Keywords

  • cytokines
  • endothelium
  • glomerulus
  • prostaglandins
  • proteinuria

ASJC Scopus subject areas

  • Nephrology

Cite this

The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis. / Madaio, Michael P.; Czikora, Istvan; Kvirkvelia, Nino; McMenamin, Malgorzata; Yue, Qiang; Liu, Ting; Flores Toque, Haroldo Alfredo; Sridhar, Supriya; Covington, Katherine; Alaisami, Rabei; O'Connor, Paul M; Caldwell, Robert William; Chen, Jiankang; Clauss, Matthias; Brands, Michael W; Eaton, Douglas C.; Romero Lucas, Maritza Josefina; Lucas, Rudolf.

In: Kidney International, Vol. 95, No. 6, 01.06.2019, p. 1359-1372.

Research output: Contribution to journalArticle

Madaio, Michael P. ; Czikora, Istvan ; Kvirkvelia, Nino ; McMenamin, Malgorzata ; Yue, Qiang ; Liu, Ting ; Flores Toque, Haroldo Alfredo ; Sridhar, Supriya ; Covington, Katherine ; Alaisami, Rabei ; O'Connor, Paul M ; Caldwell, Robert William ; Chen, Jiankang ; Clauss, Matthias ; Brands, Michael W ; Eaton, Douglas C. ; Romero Lucas, Maritza Josefina ; Lucas, Rudolf. / The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis. In: Kidney International. 2019 ; Vol. 95, No. 6. pp. 1359-1372.
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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 - Alaisami, Rabei

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

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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.

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