| First Author | Nowak G | Year | 2017 |
| Journal | Am J Physiol Renal Physiol | Volume | 312 |
| Issue | 1 | Pages | F109-F120 |
| PubMed ID | 27760765 | Mgi Jnum | J:283119 |
| Mgi Id | MGI:6367892 | Doi | 10.1152/ajprenal.00115.2016 |
| Citation | Nowak G, et al. (2017) Deletion of protein kinase C-epsilon attenuates mitochondrial dysfunction and ameliorates ischemic renal injury. Am J Physiol Renal Physiol 312(1):F109-F120 |
| abstractText | Previously, we documented that activation of protein kinase C-epsilon (PKC-epsilon) mediates mitochondrial dysfunction in cultured renal proximal tubule cells (RPTC). This study tested whether deletion of PKC-epsilon decreases dysfunction of renal cortical mitochondria and improves kidney function after renal ischemia. PKC-epsilon levels in mitochondria of ischemic kidneys increased 24 h after ischemia. Complex I- and complex II-coupled state 3 respirations were reduced 44 and 27%, respectively, in wild-type (WT) but unchanged and increased in PKC-epsilon-deficient (KO) mice after ischemia. Respiratory control ratio coupled to glutamate/malate oxidation decreased 50% in WT but not in KO mice. Activities of complexes I, III, and IV were decreased 59, 89, and 61%, respectively, in WT but not in KO ischemic kidneys. Proteomics revealed increases in levels of ATP synthase (alpha-subunit), complexes I and III, cytochrome oxidase, alpha-ketoglutarate dehydrogenase, and thioredoxin-dependent peroxide reductase after ischemia in KO but not in WT animals. PKC-epsilon deletion prevented ischemia-induced increases in oxidant production. Plasma creatinine levels increased 12-fold in WT and 3-fold in KO ischemic mice. PKC-epsilon deletion reduced tubular necrosis, brush border loss, and distal segment damage in ischemic kidneys. PKC-epsilon activation in hypoxic RPTC in primary culture exacerbated, whereas PKC-epsilon inhibition reduced, decreases in: 1) complex I- and complex II-coupled state 3 respirations and 2) activities of complexes I, III, and IV. We conclude that PKC-epsilon activation mediates 1) dysfunction of complexes I and III of the respiratory chain, 2) oxidant production, 3) morphological damage to the kidney, and 4) decreases in renal functions after ischemia. |
