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Am J Physiol Renal Physiol. 2014 Sep 15;307(6):F718-26. doi: 10.1152/ajprenal.00372.2013. Epub 2014 Jul 23.

Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation.

Author information

1
Department of Nephrology, Hannover Medical School, Hannover, Germany; The Transplantation Center, Affiliated Hospital, Zunyi Medical College, Zunyi, China;
2
Institute for Diagnostic and Interventional Radiology, Medical School Hannover, Hannover, Germany;
3
Department of Nephrology, Hannover Medical School, Hannover, Germany;
4
Centre for Paediatrics and Adolescent Medicine, Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
5
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada;
6
Department of Nephrology, Hannover Medical School, Hannover, Germany; Phenos GmbH, Hannover, Germany;
7
Department of Nephrology, Hannover Medical School, Hannover, Germany; The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway;
8
Imaging Center, Institute for Animal Science, Medical School Hannover, Hannover, Germany; and.
9
Department of Nephrology, Hannover Medical School, Hannover, Germany; gueler.faikah@mh-hannover.de.

Abstract

Acute kidney injury (AKI) increases the risk of morbidity and mortality after major surgery and transplantation. We investigated the effect of PKC-ε deficiency on AKI and ischemic allograft damage after kidney transplantation. PKC-ε-deficient and wild type (WT) control mice were subjected to 35 min of renal pedicle clamping to induce AKI. PKC-ε deficiency was associated with a marked improvement in survival and an attenuated loss of kidney function. Furthermore, functional MRI experiments revealed better renal perfusion in PKC-ε-deficient mice than in WT mice one day after IRI. Acute tubular necrosis and neutrophil infiltration were markedly reduced in PKC-ε-deficient mice. To determine whether this resistance to ischemia-reperfusion injury resulted from changes in local renal cells or infiltrating leukocytes, we studied a life-supporting renal transplant model of ischemic graft injury. We transplanted kidneys from H(2b) PKC-ε-deficient mice (129/SV) and their corresponding WT littermates into major histocompatibility complex-incompatible H(2d) recipients (BALB/c) and induced ischemic graft injury by prolonged cold ischemia time. Recipients of WT allografts developed severe renal failure and died within 10 days of transplantation. Recipients of PKC-ε-deficient allografts had better renal function and survival; they had less generation of ROS and upregulation of proinflammatory proteins (i.e., ICAM-1, inducible nitric oxide synthase, and TNF-α) and showed less tubular epithelial cell apoptosis and inflammation in their allografts. These data suggest that local renal PKC-ε expression mediates proapoptotic and proinflammatory signaling and that an inhibitor of PKC-ε signaling could be used to prevent hypoxia-induced AKI.

KEYWORDS:

allograft rejection; functional magnetic resonance imaging; inflammation; ischemia-reperfusion injury; protein kinase C-ε; transplantation; tumor necrosis factor-α

PMID:
25056349
DOI:
10.1152/ajprenal.00372.2013
[Indexed for MEDLINE]
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