A Cell-Penetrating Peptide That Blocks Toll-Like Receptor Signaling Protects Kidneys against Ischemia-Reperfusion Injury.

Su Woong Jung,Jung-Woo Seo,Ju-Young Moon,Sangdun Choi,Seon Hwa Park,Sang-Ho Lee,Yang Gyun Kim

doi:10.3390/ijms22041627

Abstract

Renal ischemia-reperfusion injury (IRI) is involved in the majority of clinical conditions that manifest as renal function deterioration; however, specific treatment for this type of injury is still far from clinical use. Since Toll-like receptor (TLR)-mediated signaling is a key mediator of IRI, we examined the effect of a multiple-TLR-blocking peptide named TLR-inhibitory peptide 1 (TIP1), which exerts the strongest action on TLR4, on renal IRI. We subjected C57BL/6 mice to 23 min of renal pedicle clamping preceded by intraperitoneal injection with a vehicle or TIP1. Sham control mice underwent flank incision only. Mouse kidneys were harvested after 24 h of reperfusion for histology, western blot, RT-PCR, and flow cytometry analysis. Pretreatment with TIP1 lowered the magnitude of elevated plasma creatinine levels and attenuated tubular injury. TIP1 treatment also reduced mRNA expression of inflammatory cytokines and decreased apoptotic cells and oxidative stress in post-ischemic kidneys. In kidneys pretreated with TIP1, the infiltration of macrophages and T helper 17 cells was less abundant than those in the IRI only group. These results suggest that TIP1 has a potential beneficial effect in attenuating the degree of kidney damage induced by IRI.

Highlights

Ischemia-reperfusion injury (IRI) clinically manifests as acute kidney injury following shock, sepsis, or renal transplantation
In contrast to eritoran and TAK-242, which have selective specificity for Toll-like receptor 4 (TLR4), OPN301 for TLR2, and ODN2088-encapsulated nanoparticles for TLR9, we found that, in our prior in vitro study using immune cells, Toll-like receptors (TLRs)-inhibitory peptide 1 (TIP1) exerts an inhibitory action on TLR1 through TLR9, with the exception of TLR5
Our study demonstrated that TIP1 improved ischemic kidney injury and suggested a potential candidate that may be useful in clinical conditions in which IRI is involved

Summary

Introduction

Ischemia-reperfusion injury (IRI) clinically manifests as acute kidney injury following shock, sepsis, or renal transplantation. Under temporary cessation of blood supply, tubular epithelial cells are deprived of oxygen and nutrients and fall into an ATP-deficient state. The subsequent recovery of blood supply accelerates tissue injury by generating reactive oxygen species (ROS). Under these conditions, tubular epithelial cells undergo apoptosis and necrosis and release endogenous damage-associated molecular patterns, such as highmobility group box 1 (HMGB1) and biglycan [1]. The expression of TLRs is not confined to immune cells alone. TLR1, 2, 3, 4, 6, and 9 are constitutively expressed in tubular epithelial cells, whereas TLR2 and 4 are normally present in endothelial cells [2,3,4]. TLR1, 2, 4, and 6 are present on the cell surface, while TLR3 and 9 reside on the intracellular endosome

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