Effects of the antioxidant drug tempol on renal oxygenation in mice with reduced renal mass

EY Lai, Z Luo, ML Onozato… - American Journal …, 2012 - journals.physiology.org
EY Lai, Z Luo, ML Onozato, EH Rudolph, G Solis, PA Jose, A Wellstein, S Aslam, MT Quinn
American Journal of Physiology-Renal Physiology, 2012journals.physiology.org
We tested the hypothesis that reactive oxygen species (ROS) contributed to renal hypoxia in
C57BL/6 mice with ⅚ surgical reduction of renal mass (RRM). ROS can activate the
mitochondrial uncoupling protein 2 (UCP-2) and increase O2 usage. However, UCP-2 can
be inactivated by glutathionylation. Mice were fed normal (NS)-or high-salt (HS) diets, and
HS mice received the antioxidant drug tempol or vehicle for 3 mo. Since salt intake did not
affect the tubular Na+ transport per O2 consumed (TNa/QO2), further studies were confined …
We tested the hypothesis that reactive oxygen species (ROS) contributed to renal hypoxia in C57BL/6 mice with ⅚ surgical reduction of renal mass (RRM). ROS can activate the mitochondrial uncoupling protein 2 (UCP-2) and increase O2 usage. However, UCP-2 can be inactivated by glutathionylation. Mice were fed normal (NS)- or high-salt (HS) diets, and HS mice received the antioxidant drug tempol or vehicle for 3 mo. Since salt intake did not affect the tubular Na+ transport per O2 consumed (TNa/QO2), further studies were confined to HS mice. RRM mice had increased excretion of 8-isoprostane F and H2O2, renal expression of UCP-2 and renal O2 extraction, and reduced TNa/QO2 (sham: 20 ± 2 vs. RRM: 10 ± 1 μmol/μmol; P < 0.05) and cortical Po2 (sham: 43 ± 2, RRM: 29 ± 2 mmHg; P < 0.02). Tempol normalized all these parameters while further increasing compensatory renal growth and glomerular volume. RRM mice had preserved blood pressure, glomeruli, and patchy tubulointerstitial fibrosis. The patterns of protein expression in the renal cortex suggested that RRM kidneys had increased ROS from upregulated p22phox, NOX-2, and -4 and that ROS-dependent increases in UCP-2 led to hypoxia that activated transforming growth factor-β whereas erythroid-related factor 2 (Nrf-2), glutathione peroxidase-1, and glutathione-S-transferase mu-1 were upregulated independently of ROS. We conclude that RRM activated distinct processes: a ROS-dependent activation of UCP-2 leading to inefficient renal O2 usage and cortical hypoxia that was offset by Nrf-2-dependent glutathionylation. Thus hypoxia in RRM may be the outcome of NADPH oxidase-initiated ROS generation, leading to mitochondrial uncoupling counteracted by defense pathways coordinated by Nrf-2.
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