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

• Published in: American journal of physiology. Heart and circulatory physiology 2007-12, Vol.293 (6), p.H3542-H3549
• Main Authors: Salom, Miguel G, Nieto Ceron, Susana, Rodriguez, Francisca, Lopez, Bernardo, Hernandez, Isabel, Gil Martinez, Jose, Martinez Losa, Adoracion, Fenoy, Francisco J
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - etiology; Acute Kidney Injury - metabolism; Acute Kidney Injury - physiopathology; Acute Kidney Injury - prevention & control; Animals; Cobalt - pharmacology; Cobalt - therapeutic use; Disease Models, Animal; Enzyme Induction; Enzyme Inhibitors - pharmacology; Glomerular Filtration Rate - drug effects; Heme Oxygenase (Decyclizing) - antagonists & inhibitors; Heme Oxygenase (Decyclizing) - biosynthesis; Ischemia - complications; Ischemia - drug therapy; Ischemia - metabolism; Ischemia - physiopathology; Isoenzymes - metabolism; Kidney Medulla - blood supply; Kidney Medulla - drug effects; Kidney Medulla - enzymology; Kidney Medulla - physiopathology; Male; Metalloporphyrins - pharmacology; Nitric Oxide - metabolism; Nitric Oxide Synthase - metabolism; Peroxynitrous Acid - metabolism; Rats; Rats, Sprague-Dawley; Renal Circulation - drug effects; Reperfusion Injury - etiology; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; Reperfusion Injury - prevention & control; Sulfhydryl Compounds - metabolism; Time Factors
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00977.2007

1 Departamento de Fisiología, Facultad de Medicina, Universidad de Murcia and 2 Servicio de Análisis Clínicos, Unidad de Investigación, 3 Servicio de Cirugía, and 4 Servicio de Nefrología, Hospital Universitario "Virgen de la Arrixaca," Murcia, Spain Submitted 23 August 2007 ; accepted in final form 19 September 2007 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 (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 µl·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. cobalt chloride; nitric oxide stores; Western blot; nitric oxide synthase; peroxynitrite amperometry; nitric oxide voltammetry Address for reprint requests and other correspondence: M. G. Salom, Departamento de Fisiología, Facultad de Medicina, 30100 Murcia, Spain (e-mail: mgsalom{at}um.es )