MedicalResearch.com Interview with:
Rudolf Lucas, PhD
Professor Pharmacology and Toxicology
Vascular Biology Center, Division of Pulmonary Medicine
Michael P. Madaio, MD
Sydenstricker Professor and Chairman
Department of Medicine
Medical College of Georgia
Augusta, Georgia 30912, USA.
MedicalResearch.com: What is the background for this study?
Response: The pro-inflammatory cytokine tumor necrosis factor (TNF) is a crucial mediator of glomerulonephritis, but the cytokine is also important in defense to bacterial infections. As such, chronically inhibiting TNF, using soluble TNF receptor constructs or neutralizing anti-TNF antibodies can promote infection.
In this study, we wanted to develop a novel therapeutic strategy to specifically inhibiting deleterious TNF signaling, while preserving the beneficial anti-bacterial actions of the cytokine.
MedicalResearch.com: What are the main findings?
Response: We demonstrate that the TNF-derived TIP peptide (a.k.a. Solnatide, AP301), which mimics the lectin-like domain of the cytokine (Lucas et al., Science 1994) and which does not affect TNF’s anti-bacterial effects (Lucas et al., Infect. Immun. 1997), significantly blunts renal inflammation and proteinuria in a murine model of nephrotoxic nephritis (NTN) through upregulating protective mechanisms in glomerular endothelial cells, involving nitric oxide and prostaglandin E2 (Kvirkvelia et al., Am. J. Physiol. Renal Physiol. 2013; Madaio et al., Kidney Int. 2019).
In collaboration with Dr. Doug Eaton (Dept. of Medicine, Emory), we show that this protective activity of the peptide occurs mainly through direct binding to the alphasubunit and activation of the epithelial sodium channel, which is expressed in glomerular endothelial cells. Local glomerular delivery of the peptide, coupled to the anti-α3(IV)NC1 antibody (Kvirkvelia et al., Am. J. Physiol. Renal Physiol. 2015) reduces kidney pathology in a moderate NTN model and significantly blunts mortality by 80% in a severe NTN model. Using telemetry (Dr. Michael Brands, MCG), we demonstrate that the TIP peptide does not increase mean arterial blood pressure and even reduces it under high salt diet conditions combined with nephrotoxic nephritis.
MedicalResearch.com: What should readers take away from your report?
Response: Since the TIP peptide has already been evaluated in clinical trials in patients with acute lung injury (Krenn et al., Crit. Care 2017) and lung transplantation (Aigner et al., J. Heart Lung Transpl. 2018), these data can foster the development of novel therapeutic agents for the treatment of glomerulonephritis that mainly affect resident glomerular cells.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Since we demonstrate in collaboration with Dr. Jian-Kang Chen (MCG) that the TIP peptide also blunts TH17 infiltration during the autologous phase of low dose NTN (Madaio et al., Kidney Int. 2019), in future research we would like to investigate its therapeutic potential for treatment of lupus nephritis. Moreover, we will further characterize the role of endothelial ENaC-alpha in protection from renal inflammation, using transgenic mouse models.
The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis.
Madaio, Michael P. et al.
Kidney International , Volume 0 , Issue 0 ,
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