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

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

  • PLoS One. 2015 Jan 24;10(1):e0115709. doi: 10.1371/journal.pone.0115709.
Faikah Gueler 1,  Nelli Shushakova 2,  Michael Mengel 3,  Katja Hueper 4,  Rongjun Chen 5,  Xiaokun Liu 6,  Joon-Keun Park 1,  Hermann Haller 1,  Gert Wensvoort 7,  Song Rong 8
Affiliations

Affiliations

  • 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.
PMID: 25617900 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.

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