Decreased kidney oxygenation due to mitochondrial uncoupling: a mechanism to injury after renal transplantation
D.A. Papazova, M. Friederich-Persson, J.A. Joles Jaap, M.C. Verhaar
Moderator(s): H.J.P.M. Koenen en H.G. Otten
Location(s): Breezaal
Category:
Severe ischemia/reperfusion injury (IRI) is the most common cause for delayed graft function and chronic allograft dysfunction. Lower renal oxygenation, regarded as part of a common pathway to nephropathy, is observed after IRI, indicating a disturbed role of oxygen handling in these kidneys. We hypothesize that mitochondrial uncoupling via uncoupling proteins (UCP) increases oxygen consumption and contributes to decreased renal oxygenation after transplantation. Male Lewis rats were left untreated as 2K-controls (CON, N=6), uninephrectomized as 1K-controls (UNX, N=7), or underwent syngenic renal transplantation (Tx, N=6). Tx was performed with end-to-end anastomoses of vessels and ureter, with 30 min and 30-40 min cold and warm ischemia time respectively and subsequent removal of the contralateral kidney. Two weeks after Tx, renal function was evaluated as glomerular filtration rate (GFR: inulin clearance), renal plasma flow (RPF: PAH clearance), renal blood flow (RBF: PAH clearance/1 - HCT), kidney oxygen tension (pO2) and consumption (QO2). Mitochondrial uncoupling was evaluated in a separate cohort (N=6 per group). Tx resulted in increased GFR (2.4±0.2 vs. 1.8±0.4 ml/min/kidney, P<0.05), RPF (9.4±0.8 vs. 6.9±0.1 ml/min/kidney, P<0.01), RBF (14.4±1.4 vs. 11.4 ± 1.7 ml/min/kidney p<0.01) but did not affect mean arterial pressure (98±11 vs. 99±5 mmHg, ns) and UNX changed none of those parameters in comparison to CON. Tx also increased kidney QO2 (54.4±15.7 vs. 30.9±13.9, P<0.05 µmol/min) and decreased pO2 (30.3±12.6 vs. 58.8±15.3 µM, P<0.01) compared to CON, changes not observed in UNX vs. CON. Furthermore, Tx, but not UNX alone, resulted in mitochondrial uncoupling evident as a larger decrease in oxygen consumption after UCP blockade (-15.8±2.1 vs. -1.9±0.8 pmol O2/s, P<0.05). The present study demonstrates that mitochondrial uncoupling occurs early after Tx and is associated with decreased kidney oxygen consumption and oxygen tension despite hyperperfusion. This early hypoxia may contribute to progressive chronic damage in transplanted kidneys.