Protective Effects of HBSP on Ischemia Reperfusion and Cyclosporine A Induced Renal Injury

Journal of Immunology Research, Oct 2013

Ischemia reperfusion (IR) and cyclosporine A (CsA) injuries are unavoidable in kidney transplantation and are associated with allograft dysfunction. Herein, the effect and mechanism of a novel tissue protective peptide, helix B surface peptide (HBSP) derived from erythropoietin, were investigated in a rat model. The right kidney was subjected to 45 min ischemia, followed by left nephrectomy and 2-week reperfusion, with or without daily treatment of CsA 25 mg/kg and/or HBSP 8 nmol/kg. Blood urea nitrogen was increased by CsA but decreased by HBSP at 1 week and 2 weeks, while the same changes were revealed in urinary protein/creatinine only at 2 weeks. HBSP also significantly ameliorated tubulointerstitial damage and interstitial fibrosis, which were gradually increased by IR and CsA. In addition, apoptotic cells, infiltrated inflammatory cells, and active caspase-3

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Protective Effects of HBSP on Ischemia Reperfusion and Cyclosporine A Induced Renal Injury

Protective Effects of HBSP on Ischemia Reperfusion and Cyclosporine A Induced Renal Injury Yuanyuan Wu,1 Junlin Zhang,2 Feng Liu,2 Cheng Yang,3 Yufang Zhang,4 Aifen Liu,4 Lan Shi,2 Yajun Wu,2 Tongyu Zhu,3 Michael L. Nicholson,5 Yaping Fan,2 and Bin Yang2,4,5 1Department of Pathology and Comparative Medicine Institute, University of Nantong, Nantong, Jiangsu 226001, China 2Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China 3Department of Urology, Zhongshan Hospital, Fudan University and Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China 4Medical Research Centre, University of Nantong, Nantong, Jiangsu 226001, China 5Transplant Group, Department of Infection, Immunity and Inflammation, University of Leicester and Leicester General Hospital, University Hospitals of Leicester, Leicester LE5 4PW, UK Received 26 June 2013; Revised 17 August 2013; Accepted 3 September 2013 Academic Editor: Qiquan Sun Copyright © 2013 Yuanyuan Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Ischemia reperfusion (IR) and cyclosporine A (CsA) injuries are unavoidable in kidney transplantation and are associated with allograft dysfunction. Herein, the effect and mechanism of a novel tissue protective peptide, helix B surface peptide (HBSP) derived from erythropoietin, were investigated in a rat model. The right kidney was subjected to 45 min ischemia, followed by left nephrectomy and 2-week reperfusion, with or without daily treatment of CsA 25 mg/kg and/or HBSP 8 nmol/kg. Blood urea nitrogen was increased by CsA but decreased by HBSP at 1 week and 2 weeks, while the same changes were revealed in urinary protein/creatinine only at 2 weeks. HBSP also significantly ameliorated tubulointerstitial damage and interstitial fibrosis, which were gradually increased by IR and CsA. In addition, apoptotic cells, infiltrated inflammatory cells, and active caspase-3+ cells were greatly reduced by HBSP in the both IR and IR + CsA groups. The 17 kD active caspase-3 protein was decreased by HBSP in the IR and IR + CsA kidneys, with decreased mRNA only in the IR + CsA kidneys. Taken together, it has been demonstrated, for the first time, that HBSP effectively improved renal function and tissue damage caused by IR and/or CsA, which might be through reducing caspase-3 activation and synthesis, apoptosis, and inflammation. 1. Introduction Kidney transplantation is the best treatment for patients with end-stage renal disease. Ischemia reperfusion (IR) injury is associated with delayed graft function, acute rejection, and chronic allograft dysfunction [1, 2]. The principle approaches to improve allograft survival have focused largely on the inhibition of immune cell activation in recipients [3], as the release of immune adjuvants initiating by IR injury promotes adaptive alloimmune responses and rejection. Cyclosporine A (CsA) is a mainstay immunosuppressant following kidney transplantation, but its nephrotoxicity limits clinical application [4]. The mechanism IR and/or CsA induced injury has been intensively studied but still not been fully understood. IR and CsA directly damage tubular epithelial cells and cause interstitial fibrosis through upregulating TGF-β1 dependent pathways, which consequently results in apoptosis and inflammation [5]. The activation of caspase-3 was revealed in the injury induced by IR and/or immunosuppressants including CsA [6], which plays crucial roles in apoptosis and inflammation, either improving renal function and structure through resolving inflammation and remodeling or leading to renal cell deletion and fibrosis [7, 8]. Since the early 1990s, erythropoietin (EPO) has been found to protect different organs including the brain, heart, and kidney against IR injury [9]. EPO protects tissues through a heterodimer composed of EPO receptor and β-common receptor (βcR), which is pharmacologically distinct from the homodimer receptor that is known to mediate erythropoiesis [10]. Our own studies demonstrated the renoprotection of EPO against IR injury by decreasing tubular cell apoptosis but promoting inflammatory cell apoptosis [11, 12]. The tissue protection, however, requires large dosage of EPO, which often causes hypertension and thrombosis in vivo [13, 14]. Therefore, a novel helix B surface peptide (HBSP) that interacts only with the heterodimer receptor has been developed, which is composed of 11 amino acids (QEQLERALNSS) derived from the aqueous face of helix B in EPO 3D structure. The tissue protective activities of HBSP comparable with EPO were demonstrated in a variety of biological settings [15]. HBSP has been shown to reduce apoptotic cardiomyocytes [16] and to activate critical survival signaling pathways [17]. In this study, the effects of HBSP were f (...truncated)


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Yuanyuan Wu, Junlin Zhang, Feng Liu, Cheng Yang, Yufang Zhang, Aifen Liu, Lan Shi, Yajun Wu, Tongyu Zhu, Michael L. Nicholson, Yaping Fan, Bin Yang. Protective Effects of HBSP on Ischemia Reperfusion and Cyclosporine A Induced Renal Injury, Journal of Immunology Research, 2013, 2013, DOI: 10.1155/2013/758159