title: Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation.
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.
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany; The Transplantation Center, Affiliated Hospital, Zunyi Medical College, Zunyi, China;
authors: Song
authors: S
authors: Rong
authors: Institute for Diagnostic and Interventional Radiology, Medical School Hannover, Hannover, Germany;
authors: Katja
authors: K
authors: Hueper
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany;
authors: Torsten
authors: T
authors: Kirsch
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany;
authors: Robert
authors: R
authors: Greite
authors: Centre for Paediatrics and Adolescent Medicine, Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors: Christian
authors: C
authors: Klemann
authors: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada;
authors: Michael
authors: M
authors: Mengel
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany;
authors: Matthias
authors: M
authors: Meier
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany; Phenos GmbH, Hannover, Germany;
authors: Jan
authors: J
authors: Menne
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany; The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway;
authors: Michael
authors: M
authors: Leitges
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany;
authors: Nathan
authors: N
authors: Susnik
authors: Imaging Center, Institute for Animal Science, Medical School Hannover, Hannover, Germany; and.
authors: Martin
authors: M
authors: Meier
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany;
authors: Hermann
authors: H
authors: Haller
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany; Phenos GmbH, Hannover, Germany;
authors: Nelli
authors: N
authors: Shushakova
authors: Department of Nephrology, Hannover Medical School, Hannover, Germany; gueler.faikah@mh-hannover.de.
authors: Faikah
authors: F
authors: Gueler
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology*; D064591:Allografts / Q000201:enzymology; D000818:Animals; D017209:Apoptosis; D006085:Graft Survival; D007249:Inflammation / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C090509:Icam1 protein, mouse; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C497256:Prkce protein, mouse; D051744:Protein Kinase C-epsilon
keywords: allograft rejection; functional magnetic resonance imaging; inflammation; ischemia-reperfusion injury; protein kinase C-ε; transplantation; tumor necrosis factor-α