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

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


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.

MeSH terms

  • Acute Kidney Injury / enzymology*
  • Allografts / enzymology
  • Animals
  • Apoptosis
  • Graft Survival
  • Inflammation / metabolism
  • Intercellular Adhesion Molecule-1 / metabolism
  • Kidney Function Tests
  • Kidney Transplantation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Protein Kinase C-epsilon / metabolism*
  • Reactive Oxygen Species / metabolism
  • Reperfusion Injury / enzymology*
  • Tumor Necrosis Factor-alpha / metabolism


  • Icam1 protein, mouse
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Prkce protein, mouse
  • Protein Kinase C-epsilon