Heme oxygenase-1 induction improves ischemic renal failure: role of nitric oxide and peroxynitrite

The present study evaluated the effects of heme oxygenase-1 (HO-1) induction on the changes in renal outer medullary nitric oxide (NO) and peroxynitrite levels during 45-min renal ischemia and 30-min reperfusion in anesthetized rats. Glomerular filtration rate (GFR), outer medullary blood flow (OMBF), HO and nitric oxide synthase (NOS) isoform expression, and renal low-molecular-weight thiols (–SH) were also determined. During ischemia significant increases in NO levels and peroxynitrite signal were observed (from 832.1 ± 129.3 to 2,928.6 ± 502.0 nM and from 3.8 ± 0.7 to 9.0 ± 1.6 nA before and during ischemia, respectively) that dropped to preischemic levels during reperfusion. OMBF and –SH significantly decreased after 30 min of reperfusion. Twenty-four hours later, an acute renal failure was observed (GFR 923.0 ± 66.0 and 253.6 ± 55.3 μl·min−1·g kidney wt−1 in sham-operated and ischemic kidneys, respectively; P < 0.05). The induction of HO-1 (CoCl2 60 mg/kg sc, 24 h before ischemia) decreased basal NO concentration (99.7 ± 41.0 nM), although endothelial and neuronal NOS expression were slightly increased. CoCl2 administration also blunted the ischemic increase in NO and peroxynitrite (maximum values of 1,315.6 ± 445.6 nM and 6.3 ± 0.5 nA, respectively; P < 0.05), preserving postischemic OMBF and GFR (686.4 ± 45.2 μl·min−1·g kidney wt−1). These beneficial effects of CoCl2 on ischemic acute renal failure seem to be due to HO-1 induction, because they were abolished by stannous mesoporphyrin, a HO inhibitor. In conclusion, HO-1 induction has a protective effect on ischemic renal failure that seems to be partially mediated by decreasing the excessive production of NO with the subsequent reduction in peroxynitrite formation observed during ischemia.