A novel therapy to attenuate acute kidney injury and ischemic allograft damage after allogenic kidney transplantation in mice.

Faikah Gueler,Joon-Keun Park,Michael Mengel,Gert Wensvoort,Rongjun Chen,Hermann Haller,Nelli Shushakova,Katja Hueper,Xiaokun Liu,Song Rong

doi:10.1371/journal.pone.0115709

Abstract

Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20–50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

Highlights

Ischemia reperfusion injury (IRI) causes acute kidney injury (AKI) with tubular and endothelial damage and leads to an early loss of peritubular capillaries (PTC) [1], decreased renal perfusion, and inflammation and fibrosis of the kidney [2]
With EA-230 doses between 30–50 mg/kg survival reached 56–62% (p
In this study we investigated a novel therapeutic approach to improve outcome after IRI and ischemic allograft damage

Summary

Introduction

Ischemia reperfusion injury (IRI) causes acute kidney injury (AKI) with tubular and endothelial damage and leads to an early loss of peritubular capillaries (PTC) [1], decreased renal perfusion, and inflammation and fibrosis of the kidney [2]. Ischemic allograft damage is correlated with impaired microcirculation in the peritubular capillaries [3] resulting in delayed graft function (DGF) [4]. DGF is a form of acute kidney injury (AKI) causing post-transplantation oliguria and increased allograft immunogenicity. It is associated with an increased risk of acute rejection episodes, and decreased longterm survival [5]. AKI contributes to increased morbidity and mortality following the transplantation of organs other than the kidney. In lung transplantation [6,7], and nonmyeloablative hematopoietic cell transplantation AKI is seen in more than 50% of patients and it increases the risk of mortality [8]

Methods

Results

Conclusion