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

Abstract

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 microl.min(-1).g kidney wt(-1) in sham-operated and ischemic kidneys, respectively; P < 0.05). The induction of HO-1 (CoCl(2) 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. CoCl(2) 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 microl.min(-1).g kidney wt(-1)). These beneficial effects of CoCl(2) 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.

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

“…HO-1 produces carbon monoxide (a potent vasodilator) while degrading heme, which may preserve tissue blood flow during reperfusion (191). Thus, it has been suggested that the induction of HO-1 can protect the kidney from ischemic damage by decreasing oxidative damage and NO generation (192,193). Finally, in addition to its anti-apoptotic properties, EPO may restore renal microcirculation, and thus protect the kidney from ischemic damage (176), by stimulating the mobilization and differentiation of progenitor cells toward an endothelial phenotype (194) and inducing NO release from eNOS (195).…”

Oxidative and Nitrosative Stress in the Ischemic Acute Renal Failure

“…However, when present in excess, a condition known as oxidative stress, they exert deleterious effects including lipid peroxidation, oxidative DNA damage and protein oxidation and nitration that collectively lead to progressive endothelial and tubular cells damage described in the precedent section. Generation of high levels of reactive oxygen species during renal ischemia/reperfusion have been confirmed directly (Zweier et al, 1994;Salom et al, 2007) and indirectly by measuring the effects of oxidants on lipids, proteins and DNA and by determining the beneficial effects of free radicals scavenging with antioxidant enzymes like superoxide dismutase or catalase or with antioxidants allopurinol (a xanthine oxidase inhibitor), tempol (an superoxide dismutase mimetic), N-acetyl-L-cysteine (an antioxidant), or dimethylthiourea (a hydroxyl radical scavenger) (Chatterjee et al, 2000;López-Conesa et al, 2001;Noiri et al, 2001;Tsuji et al, 2009). However, these compounds also scavenge or inhibit the formation of peroxynitrite (ONOO¯) a highly reactive chemical specie derived from nitric oxide and superoxide.…”

“…HO-1 prior to the induction of I/R results in functional protection in ischemic renal failure (Maines, 1999), which is partially mediated by reduction of oxidative and nitrosative stress during ischemia (Salom et al, 2007). Moreover, in the same way that HO metabolites maintain renal medullary perfusion (Zou et al, 2000), glomerular filtration rate and renal blood flow (Arregui B, 2004) in physiological conditions, HO-1 induction preserved postischemic medullary blood flow and GFR, in ischemic renal failure, (Salom et al, 2007).…”

“…HO-1 prior to the induction of I/R results in functional protection in ischemic renal failure (Maines, 1999), which is partially mediated by reduction of oxidative and nitrosative stress during ischemia (Salom et al, 2007). Moreover, in the same way that HO metabolites maintain renal medullary perfusion (Zou et al, 2000), glomerular filtration rate and renal blood flow (Arregui B, 2004) in physiological conditions, HO-1 induction preserved postischemic medullary blood flow and GFR, in ischemic renal failure, (Salom et al, 2007). Overall, HO-1 induction might have multiple beneficial functions in I/R injury a) by reducing oxidative stress insults b) by preserving alteration of renal hemodynamic which contributes greatly to the subsequent renal failure and c) via suppression of the immune response through its anti-inflammatory actions, (Kotsch et al, 2007).…”

“…Moreover, studies combining inhaled CO and infused bilirubin in rat renal transplantation demonstrated synergistic effects on glomerular filtration rate and renal blood flow (Nakao et al, 2005) suggesting also a role of bilirubin production in cytoprotection against ischemia/reperfusion injury. Finally, HO induction, through a variety of mechanisms, can reduce NO synthesis and, consequently, diminish augmented peroxynitrite formation during ischemia (Salom MG, 2007).…”