TY - JOUR
T1 - Aberrant utilization of nitric oxide and regulation of soluble guanylate cyclase in rat diabetic retinopathy
AU - Schaefer, Silke
AU - Kajimura, Mayumi
AU - Tsuyama, Shingo
AU - Uchida, Koji
AU - Sato, Eisuke
AU - Inoue, Masayasu
AU - Suematsu, Makoto
AU - Watanabe, Kenji
PY - 2003/8
Y1 - 2003/8
N2 - Although nitric oxide (NO) was shown not only to exert biological activities through activation of soluble guanylate cyclase (sGC), but also to cause oxidative stress, mechanisms for switching these pathways are unknown. This study aimed to examine aberrant utilization of NO under disease conditions such as diabetes mellitus. Diabetes was induced in male Wistar rats by injecting streptozotocin (STZ; 50 mg/kg body weight, i.p.). Retina was perfusion-fixed for immunohistochemistry to detect the gas-mediated activation of sGC by anti-sGC antibodies that are function-sensitive [monoclonal antibody (MoAb) 3221] and -insensitive (MoAb28131). Regional lipid peroxidation was also examined by an anti-acrolein MoAb. At 6 weeks after STZ injection, inducible NO synthase induction became evident, coinciding with the overproduction of nitrotyrosine, followed by that of acrolein. Despite such NO overproduction, sGC did not exhibit any notable activation. When STZ-treated animals were posttreated with a derivative of superoxide dismutase that stays in circulation without undergoing renal ultrafiltration, immunoreactivities to MoAb3221 but not to MoAb28131 increased markedly in diabetic retina, suggesting that superoxide cancels free NO for local sGC activation. These results provide evidence of aberrant utilization of NO and suggest that superoxide plays a role in interfering with NO-mediated sGC activation for phototransducing events in this neural tissue.
AB - Although nitric oxide (NO) was shown not only to exert biological activities through activation of soluble guanylate cyclase (sGC), but also to cause oxidative stress, mechanisms for switching these pathways are unknown. This study aimed to examine aberrant utilization of NO under disease conditions such as diabetes mellitus. Diabetes was induced in male Wistar rats by injecting streptozotocin (STZ; 50 mg/kg body weight, i.p.). Retina was perfusion-fixed for immunohistochemistry to detect the gas-mediated activation of sGC by anti-sGC antibodies that are function-sensitive [monoclonal antibody (MoAb) 3221] and -insensitive (MoAb28131). Regional lipid peroxidation was also examined by an anti-acrolein MoAb. At 6 weeks after STZ injection, inducible NO synthase induction became evident, coinciding with the overproduction of nitrotyrosine, followed by that of acrolein. Despite such NO overproduction, sGC did not exhibit any notable activation. When STZ-treated animals were posttreated with a derivative of superoxide dismutase that stays in circulation without undergoing renal ultrafiltration, immunoreactivities to MoAb3221 but not to MoAb28131 increased markedly in diabetic retina, suggesting that superoxide cancels free NO for local sGC activation. These results provide evidence of aberrant utilization of NO and suggest that superoxide plays a role in interfering with NO-mediated sGC activation for phototransducing events in this neural tissue.
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U2 - 10.1089/152308603768295203
DO - 10.1089/152308603768295203
M3 - Article
C2 - 13678534
AN - SCOPUS:0043264804
SN - 1523-0864
VL - 5
SP - 457
EP - 465
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 4
ER -