Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension

摘要

Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (P_(O_2)). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney hypoxia. Lewis rats underwent syngenic renal transplantation (TX) and contralateral nephrectomy. Controls were uninephrecto-mized (IK-CON) or left untreated (2K-CON). After 7 days, urinary excretion of protein and thiobarbituric acid-reactive substances were measured, and after 14 days glomerular filtration rate (GFR), renal blood flow, whole kidney Q_(O_2), cortical P_(O_2), kidney cortex mitochondrial uncoupling, renal oxidative damage, and tubulointerstitial injury were assessed. TX, compared with IK-CON, resulted in mitochondrial uncoupling mediated via uncoupling protein-2 (16 ± 3.3 vs. 0.9 ± 0.4 pmol O_2·s~(-1)·mg protein~(-1), P < 0.05) and increased whole kidney Q_(O_2) (55 ± 16 vs. 33 ± 10 mumol O_2/min, P < 0.05). Corticomedullary P_(O_2) was lower in TX compared with IK-CON (30 ± 13 vs. 47 ± 4 muM, P < 0.05) whereas no significant difference was observed between 2K-CON and IK-CON rats. Proteinuria, oxidative damage, and the tubulointerstitial injury score were not significantly different in IK-CON and TX. Treatment of donors for 5 days with mito-TEMPO reduced mitochondrial uncoupling but did not affect renal hemodynamics, Q_(O_2), P_(O_2), or injury. Collectively, our results demonstrate increased mitochondrial uncoupling as an early event after experimental renal transplantation associated with increased oxygen consumption and kidney hypoxia in the absence of increases in markers of damage.