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

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 a 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.Kidney International (2019) 95, 1359-1372; https://doi.

Dichotomous Role of Tumor Necrosis Factor in Pulmonary Barrier Function and Alveolar Fluid Clearance

“…In this model, local immune deposits in the glomeruli generate TNF, which activates pro-inflammatory pathways in both glomerular endothelial cells and podocytes. Intraperitoneal treatment with TIP peptide in this model significantly reduces inflammation (reduced systemic and local pro-inflammatory cytokine generation, and reduced renal leukocyte infiltration), as well as proteinuria and blood urea nitrogen ( Madaio et al, 2019 ). TIP peptide also increases PGE 2 generation in glomerular endothelial cells, which in turn promotes eNOS-dependent NO generation and barrier function ( Figure 4 ).…”

“…Indeed, in sharp contrast to the TNFR1 binding site, the lectin-like domain of TNF, mimicked by the TIP peptide (a.k.a. Solnatide, AP301), can activate amiloride-sensitive Na + uptake in alveolar epithelial cells, as well as in lung and glomerular MVEC, which also express all ENaC subunits ( Hribar et al, 1999 ; Elia et al, 2003 ; Braun et al, 2005 ; Madaio et al, 2019 ). This effect of the lectin-like domain of TNF occurs even in cells lacking both TNF receptors ( Hribar et al, 1999 ) thus clearly documenting that the TIP peptide binds to partners different from the TNF receptors.…”

“…In view of promising data resulting from preclinical studies of TIP peptide performed by others and our group in several animal species, including mice, rats, rabbits and pigs ( Elia et al, 2003 ; Braun et al, 2005 ; Hamacher et al, 2010 ; Madaio et al, 2019 ), clinical trials assessing safety and efficacy of TIP peptide (a.k.a. Solnatide, AP301) organized by APEPTICO, Vienna, Austria have been conducted at the Hospital of the Medical University Vienna, Austria.…”

Pretreatment with S-Nitrosoglutathione Attenuates Septic Acute Kidney Injury in Rats by Inhibiting Inflammation, Oxidation, and Apoptosis

“…It is well known that inflammation runs through the entire pathogenesis of sepsis, and the release of inflammatory factors can promote the occurrence and development of AKI [ 13 ]. In the early stage of sepsis, the proinflammatory mediators TNF- α and IL-1 β are released and are highly toxic to the body [ 14 ].…”

Impact of Bacterial Toxins in the Lungs

“…They moreover induce the release of anti-inflammatory and repair factors, including transforming growth factor β1 (TGF-β1), prostaglandin E 2 (PGE 2 ), and platelet-activating factor (PAF) [42][43][44][45]. Although PGE 2 was shown to be involved in both pro-and anti-inflammatory activities, its capacity to activate endothelial nitric oxide synthase (eNOS)-mediated nitric oxide generation was shown to significantly blunt endothelial leukocyte interactions [46,47]. Moreover, mice defective in microsomal prostaglandin E synthase-1, a key enzyme in PGE 2 synthesis, were shown to have significantly increased lethality and a defective pulmonary clearance of Streptococcus pneumoniae [48].…”