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PLoS One. 2015 Jan 24;10(1):e0115709. doi: 10.1371/journal.pone.0115709. eCollection 2015.

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

Author information

1
Department of Nephrology, Hannover Medical School, Hannover, Germany.
2
Department of Nephrology, Hannover Medical School, Hannover, Germany; Phenos GmbH, Hannover, Germany.
3
Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Canada.
4
Diagnostic and Investigative Radiology, Hannover Medical School, Hannover, Germany.
5
Department of Nephrology, Hannover Medical School, Hannover, Germany; The kidney disease centre of the First Affiliated Hospital, Zhejiang University, Hangzhou, China.
6
Department of Nephrology, Hannover Medical School, Hannover, Germany; Department of Gastrointestinal Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, China.
7
Exponential Biotherapies Inc., The Hague, The Netherlands.
8
Department of Nephrology, Hannover Medical School, Hannover, Germany; Phenos GmbH, Hannover, Germany; The Transplantation Center of the affiliated hospital, Zunyi Medical College, Zunyi, China.

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.

PMID:
25617900
PMCID:
PMC4305280
DOI:
10.1371/journal.pone.0115709
[Indexed for MEDLINE]
Free PMC Article

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